A 4+3 cycloaddition approach to the spatane ring system

Article abstract of DOI:10.1016/S0040-4039(01)01012-7

The adduct of dichloroketene and cyclopentene was converted to a tricyclo[5.3.0.0^2,6]decane ring system using a 4+3 cycloaddition reaction followed by a quasi-Favorskii rearrangement as the key steps.

Full text of DOI:10.1016/S0040-4039(01)01012-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5593–5595
A 4+3 cycloaddition approach to the spatane ring system
Michael Harmata* and Paitoon Rashatasakhon
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
Received 17 April 2001; revised 23 May 2001; accepted 4 June 2001
2,6
Abstract—The adduct of dichloroketene and cyclopentene was converted to a tricyclo[5.3.0.0 ]decane ring system using a 4+3
cycloaddition reaction followed by a quasi-Favorskii rearrangement as the key steps. © 2001 Elsevier Science Ltd. All rights
reserved.
5
The 4+3 cycloaddition reaction is a powerful method
ing several total syntheses. Our goal was to demon-
strate that we could build the spatane skeleton using a
4+3 cycloaddition reaction coupled to a quasi-Favorskii
rearrangement. This would establish the utility of more
complex cyclopentenyl cations in the 4+3 cycloaddition
reaction and also allow us to examine the potential of
the adducts to undergo nucleophilic attack and subse-
quent quasi-Favorskii rearrangement.
for the preparation of seven-membered and larger
1
rings. We have been involved in various studies of this
reaction and have recently turned our attention to the
cycloaddition reaction of halogenated, cyclic allylic
2
cations with dienes. For example, we reported that
treatment of 2,5-dibromocyclopentanone (1) with tri-
ethylamine in the presence of furan in a 1:1 mixture of
trifluoroethanol and ether as solvent resulted in the
2
b
Me
Me
formation of the cycloadduct 2.
Reaction with
methyllithium afforded the alcohol 3 in 65% yield for
the two steps. Treatment of this compound with potas-
sium hydride in THF led to the ketone 4 in 72% yield
H
Me
OH
H
Me
OH
O
O
(
Scheme 1). This quasi-Favorskii rearrangement is of
Me
Me
interest in that it allows dibromocyclopentanone to3
function as an equivalent of a substituted cyclobutene.
Me
Me
5
, stoechospermol
6, spatol
In an effort to further explore this methodology, we
have initiated a program involving the formal or total
synthesis of cyclobutane-containing natural products.
One class of such compounds includes the spatane
diterpenes, represented by stoechospermol (5) and the
We began with the dichloroketene adduct of cyclopen-
6
tene (7). Based on our previous results, we would have
preferred to use the corresponding dibromo compound.
However, we have had some difficulty handling some
dibromocyclobutanones and cyclopentanones and
anticipated that the dichloro compounds would be
4
antitumor agent spatol (6). A number of approaches to
these types of compounds have been reported, includ-
O
MeLi
65%
O
furan, TEA
Br TFE/ether
Br
O
Br
Me
Br
O
OH
1
2
3
O
KH, THF
2%
Me
7
O
4
Scheme 1. 2,5-Dibromocyclopentanone as a cyclobutene equivalent.
*
Corresponding author. Tel.: 573-882-1097; fax: 573-882-2754; e-mail: harmatam@missouri.edu
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01012-7

5
594
M. Harmata, P. Rashatasakhon / Tetrahedron Letters 42 (2001) 5593–5595
more stable. Given that our work with chloroketones
with respect to their quasi-Favorskii reaction was quite
limited, this offered us an opportunity to demonstrate
that using chlorinated precursors in our sequence could
be effective with respect to both cycloaddition and
subsequent rearrangement chemistry.
the carbonyl group which is least sterically hindered,
based on an inspection of models. Reaction of 11 with
potassium hydride in THF at room temperature gave
the aldehyde 12. Reduction of the aldehyde with
sodium borohydride gave the ring-contracted alcohol
2
b
1
3 in 91% yield over two steps (Scheme 3). This
sequence demonstrates that ketone 8 is synthetically
equivalent to cyclobutene 14.
Treatment of 7 with diazomethane afforded the ring
7
expanded product 8. This was immediately reacted
with cyclopentadiene in the presence of triethylamine in
trifluoroethanol/ether to give the cycloadducts 9 and 10
in 71% yield from 7 in a ratio of 14.5:1 (Scheme 2). The
ratio was determined by examination of the crude
The aldehyde produced in the quasi-Favorskii reaction
could be reduced directly via a Wolff–Kishner reduc-
tion but the yields thus far have been less than 50%. We
thus treated alcohol 13 with tosyl chloride and reduced
the resulting ester with lithium triethylborohydride.
This gave the alkene 15 in 80% overall yield.
1
reaction mixture by H NMR. The stereochemical
9
assignment was based on differences in the chemical
shift of the olefinic protons in 9 and 10. In 9, the
olefinic protons appear at 6.25 ppm while those of 10
appear at 6.57 ppm. The upfield shift of the protons in
Finally, in order to demonstrate that the spatane ring
system could be produced, we ozonized 15 using a
9
can be ascribed to their being in the shielding cone of
1
0
protocol introduced by Schreiber and co-workers.
the ketone carbonyl group. This feature is absent in 10.
The endo stereochemistry was thus assigned to 9. Based
This afforded the two regioisomeric ester aldehydes 16
and 17 in 90% overall yield in a ratio of 1:1.4 (Scheme
8
on other cycloadditions of related cationic species, this
4
). These regioisomers were separated and structural
result was not unexpected, though it was pleasing to
find that the chloro substituent had no untoward effect
on the outcome of the reaction.
assignments were made on the basis of NOE data.
For example, the aldehyde proton of 16 showed a
crosspeak with the aliphatic methyl group on a 2D
NOESY spectrum. This signal was absent from the
spectrum of 17. Furthermore, when a mixture of 16 and
The major cycloadduct 9 was reduced with lithium
aluminum hydride to afford the corresponding alcohol
11 with complete stereoselectivity in 94% yield. The
1
7 was oxidized and esterified, only the diester 18 was
stereochemistry of 11 was established by X-ray crystal-
lography. Assuming the reaction proceeds by nucleo-
philic addition, hydride attack does occur on the face of
isolated, suggesting that 16 and 17 are not epimers.
In summary, we have shown that the combination of a
4
+3 cycloaddition reaction followed by a quasi-
Favorskii rearrangement can provide rapid access to
the spatane ring skeleton. Efforts to apply chemistry of
this type to the total synthesis of diterpenes of the
spatane class, including spatol, are underway. Progress
CH N
TEA, C5H6
TFE/ether
2
2
Cl
Cl
Cl
7
1% (two steps)
O
Cl
8
O
7
11,12
will be reported in due course.
+
O3
1
. TsCl
2. LiBHEt3
0%
Cl
Cl
O
O
MeOH/CH Cl
1
4.5:1
2
2
9
10
CH OH
Me
2
90%
8
13
15
Scheme 2. 4+3 cycloaddition reaction of 8.
1
. Jones
. CH N
+
H
Me
CHO
H
Me
CO Me
2
2
2
89%
LAH
4%
KH
THF
2
MeO C
OHC
2
H
9
17
16
1:1.4
Cl
Cl
CHO
O
OH
9
11
12
H
Me
CO Me
NaBH4
9
1% (two steps)
MeO C
2
CH OH
2
2
14
CHO
18
13
Scheme 3. Quasi-Favorskii rearrangement of 9.
Scheme 4. Formation of the spatane skeleton from 13.

M. Harmata, P. Rashatasakhon / Tetrahedron Letters 42 (2001) 5593–5595
5595
Acknowledgements
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This work was supported by the National Science
Foundation to whom we are grateful. We thank the
National Science Foundation for partial support of the
NMR (PCM-8115599) facility at the University of Mis-
souri-Columbia and for partial funding for the pur-
chase of a 500 MHz spectrometer (CHE-8908304).
Thanks to Dr. Charles L. Barnes for the acquisition of
X-ray data.
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1
2
−
1
3015, 2925, 1756, 1435, 729 cm ; Anal. calcd for
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13
15
1
2
(13): White solid, mp 95–97°C; H NMR (250 MHz) l
6.16–6.13 (m, 1H), 6.02–5.99 (m, 1H), 3.67 (d, J=11.1
Hz, 1H), 3.08 (d, J=11.1 Hz, 1H), 2.79 (d, J=1.1 Hz,
1H), 2.64 (t, J=1.2 Hz, 1H), 2.27 (t, J=7.0 Hz, 1H),
2.03–1.77 (m, 4H), 1.74–1.63 (m, 1H), 1.61–1.45 (m,
J=3H), 1.35–1.30 (m, 2H), 1.03 (t, J=1.3 Hz, 1H);
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2983, 2874, 1389, 1129 cm ; Anal. calcd for C H O: C,
3
13
C
4
2
2
−
1
1
3
18
82.06; H, 9.53. Found: C, 82.18; H, 9.39. (18): White
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1
1
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2.29–2.22 (m, 2H), 1.97 (t, J=4.4 Hz, 1H), 1.83–1.56 (m,
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2
−
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2950, 1733, 1439, 1220, 1171 cm , Anal. calcd for
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1
3
18
1
13
12. All new compounds exhibited satisfactory H and
C
NMR and IR spectral data as well as satisfactory com-
bustion analysis or high resolution exact mass data.
.