Total synthesis of (+/-)-dihydrospiniferin-1 via a polyfluoro alkanosulfonyl fluoride induced tandem carbonium ion rearrangement reaction.

Article abstract of DOI:10.1039/b300016h

A novel polyfluoroalkanosulfonyl fluoride induced carbonium ion rearrangement reaction of gamma-hydroxymethyl cyclohexenone has been used for the total synthesis of (+/-)dihydrospiniferin 1.

Full text of DOI:10.1039/b300016h

Total synthesis of (±)-dihydrospiniferin-1 via a polyfluoro alkanosulfonyl
fluoride induced tandem carbonium ion rearrangement reaction
Ling Chen, Kai Ding and Wei-Sheng Tian*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai,
200032, China. E-mail: wstian@pub.sioc.ac.cn; Fax: 86-21-64166128; Tel: 086-021-64163300-83225
Received (in Corvallis, OR, USA) 2nd January 2003, Accepted 18th February 2003
First published as an Advance Article on the web 28th February 2003
A novel polyfluoroalkanosulfonyl fluoride induced carbon-
ium ion rearrangement reaction of g-hydroxymethyl cyclo-
hexenone has been used for the total synthesis of ( )dihy-
drospiniferin 1.
afford 10 in 80% yield upon heating with methanolic potassium
carbonate4 (Scheme 2).
We planned to use BrCH2CH(OEt)2, the equivalent of a-
halogen acetaldehyde, to introduce the side chain. Kinetic
controlled enolation of enone 10 could be realized by using
LDA10as the base at low temperature (270 °C). But the
subsequent alkylation did not occur even with the iodide due to
the poor reactivity of enol anion. Fortunately, the alkylation of
allylic bromide instead of XCH2CH(OEt)2(X = Br or I) gave
two isomers 11a and 11b in 63% and 9% yields respectively.
Treatment of 11a with LiAlH4 followed by selective oxidation
of the allylic hydroxyl with DDQ11 afforded hydroxymethyl
enone13. Ozonolysis of 13 directly furnished the undesired
ketal 14, which supported the structural assignment of 11a
(Scheme 3).
Spiniferin-1(1) is a structurally unique furanosesquiterpene,
isolated by Cimino et al. in 1975 from the Mediterranean
sponge Pleraplysilla spinifera, which is present in the Bay of
Naples.1 In 1978, its structure was reformulated as 12 and
supported by Marshall’s rational synthesis of (±)-dihydrospini-
ferin-1(2) (Fig. 1).3 Racemic 1 had also been synthesized4 by
Marshall by a similar strategy. Spiniferin-1 is the first and
unique natural product with the skeleton of 1,6-metha-
no[10]annulene up to now, although Vogel et al. prepared this
kind of annulene in 1964.5 The physical and chemical properties
of 1,6-methano[10]annulene have been described in detail since
it and its analogues were synthesized, but to the best of our
knowledge no biological information has been reported. The
biological secrets of spiniferin-1 make us interested in its total
synthesis.
As a part of our research on the reaction of poly(per)-
fluoroalkanosufonyl fluorides and their application in the
synthesis of medicines and natural products,6 we found a novel
polyfluoroalkanosulfonyl fluoride induced carbonium ion re-
arrangement reaction7 of g-hydroxymethyl cyclohexenone
recently. This rearrangement reaction provides a new and
efficient synthetic method for dihydrospiniferin-1, spiniferin-1,
as well as their analogues. In this paper, we will describe the
total synthesis of (±)-dihydrospiniferin-1 via a novel poly-
fluoroalkanosulfonyl fluoride induced carbonium ion rear-
rangement reaction of g-hydroxymethyl cyclohexenone.
Our synthetic plan relied on the construction of 1,6-metha-
no[10]annulene 3, a key intermediate in Marshall’s synthesis,3
from polyhydro-4a,8a-methanonaphthalene 4, which would be
obtained by the rearrangement of g-hydroxymethyl cyclohex-
enone 5 induced by polyfluoroalkanosulfonyl fluoride. Un-
saturated ketone 5 was simplified into a readily available
Robinson annulation product 6 and an a-halogen acetaldehyde
(Scheme 1).
Scheme 1 Retrosynthetic analysis.
The Robinson annulation product 10 was obtained according
to classical methods. The dianion8 of ethyl acetoacetate 7was
generated when treated sequentially with NaH and n-BuLi in
THF. Alkylation of the dianion with 4-bromo-2-methyl-
2-butene gave the alkylated b-keto ester 8, which was cyclized
to 2-cyclohexanone carboxylate 9 in the presence of SnCl4.9
This sterically hindered b-keto ester underwent Michael
addition when treated with a catalytic amount of freshly
prepared potassium methoxide in THF, and the resulting
Michael adduct further underwent Robinson annulation to
Scheme 2 Reagents and conditions: (a) NaH, n-BuLi, 4-bromo-2-methyl-
2-butene, THF, 0 °C, 79%; (b) SnCl4, CH2Cl2, r.t., 81%; (c) KOCH3, MVK,
0 °C; K2CO3, CH3OH, reflux, 80%; (d) LDA, allylic bromide, 278
°C?r.t., 63% (11a),9% (11b); (e) LiAlH4, THF, r.t., 76%; (f) DDQ,
benzene, r.t., 70%.
Fig. 1 Structures of spiniferin-1 and dihydrospiniferin-1.
Scheme 3 The confirmation of relative configuration of 11a.
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CHEM. COMMUN., 2003, 838–839
This journal is © The Royal Society of Chemistry 2003

washed with brine and dried. The solvent was removed under reduced
pressure and the remainder was purified by column chromatography on
silica gel to afford 40 mg (69%) of (±)-2 as a colorless oil. 1H NMR
(300MHz, CDCl3) d 7.33(d, J = 1.8Hz, 1H), 6.56(d, J = 1.5Hz,1H),
6.29(s,1H), 6.28(s,1H), 3.14(d,
1.7–1.9(m,2H), 1.3–1.5(m,1H), 1.32(s,3H), 1.14(d,J
1.05(s,3H), 0.6–0.8(m,1H); 13C NMR (75MHz, CDCl3) d 153.2, 140.3,
132.5, 129.4, 125.3, 112.2, 110.0, 109.1, 42.0, 37.8, 36.7, 35.0, 29.2, 27.1,
25.8.
J
=
10.8 Hz,1H), 2.2–2.5(m,2H),
10.8 Hz,1H),
=
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Scheme 4 Reagents and conditions: (a) HCF2CF2OCF2CF2SO2F, DBU,
THF, 0 °C; NEt3, reflux, 82%; (b) O3, 270 °C, CH3OH; Me2S, r.t., 67%; (c)
12N HCl, THF, r.t. 69%.
Using a novel poly(per)fluoroalkanosufonyl fluoride induced
tandem carbonium rearrangement which was recently found by
us, g-hydroxymethyl cyclohexenone 13 was transformed into
our desired cyclopropyl enone 15 in 82% yield†. Selective
ozonolysis12 of compound 15 furnished aldehyde 4. The latter
in the presence of 12 N HCl rearranged to cycloheptatriene 3, a
unstable intermediate, which immediately cyclized to form
(±)-2 as a colorless oil (Scheme 4). Our synthetic material has
identical 1H and 13C NMR data‡ as reported by Cimino1,2 and
Mashall.3,4
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1964, 9, 642.
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D dissertation, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 1999.
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101, 305; (b) Z. Lei, Masters dissertation. Shanghai Institute of Organic
Chemistry. Chinese Academy of Sciences. 1997; (c) L. Chen, PhD
dissertation. Shanghai Institute of Organic Chemistry, Chinese Acad-
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Notes and references
† Synthesis of key intermediate 15: To a stirred, cooled solution of 99 mg
of enone 13 (0.4 mmol) in 2.5 ml of dry THF was added 119 µl (2 eq) of
DBU and 144 µl (2 eq) of HCF2CF2OCF2CF2SO2F. The solution was
stirred for 30 min and was filtered through a short silica gel column with the
aid of 2.5 ml of THF. The combined solution was added 280 µl (5 eq.) NEt3
and was heated to reflux for 8 h. The solvent was removed under reduced
pressure and the remainder was purified by column chromatography on
silica gel to afford 75 mg (82%) of 15 as a colorless oil. IR (film): n 1666,
1640 cm21; 1H NMR (300 MHz, CDCl3): d 7.08 (s,1H), 5.77 (m,1H), 5.01
(m,2H), 2.92(m,1H), 2.84(d, J = 8.6Hz, 1H), 2.51(d, J = 8.6Hz, 1H),
1.11(s,3H), 1.10(s,3H), 0.51(d, J = 4.0Hz, 3H); EIMS: m/e 230 (M+,
100%)
‡ Procedure for the synthesis of (±)-2: To a stirred solution of 62 mg 4 (0.27
mmol) in 3 ml THF was added 0.6 ml 12 N HCl. The solution was stirred
for 1 h and was extracted with ether. The combined organic layers was
12 T. Veysoglu, L. A. Mitscher and J. K. Swayze, Synthesis, 1980, 10,
807.
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