Synthesis and derivatization of bis-nor Wieland-Miescher ketone

Article abstract of DOI:10.1055/s-2005-916025

An efficient synthesis of bis-nor Wieland-Miescher ketone and its derivatives starting from commercially available 2-allyl-2-methylcyclopenta-1,3- dione is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-916025

PAPER
3147
Synthesis and Derivatization of Bis-nor Wieland–Miescher Ketone
S
ynthesis of Bis
õ
-nor
W
ielan
n
d–Miescher
i
K
etones Kanger,*a Kristin Raudla,a Riina Aav,a Aleksander-Mati Müürisepp,a Tõnis Pehk,b Margus Loppa
a
Department of Chemistry, Faculty of Science, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia
Fax +372(6)202828; E-mail: kanger@chemnet.ee
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
b
Received 3 May 2005; revised 13 June 2005
erated from allyl halide in the presence of CsF, followed
by ozonolysis/dehydration or chlorination/oxidation pro-
cedure.8 Trost et al. have used the intramolecular Wittig
reaction for the cyclization.9 The starting enol ether for it
was obtained from the Pd-catalyzed reaction of 2-methyl-
cyclopenta-1,3-dione with 3-acetoxy-2-ethoxyprop-1-
ene. We report here a high-yield synthesis of bis-nor
Wieland–Miescher ketone 2 starting, from commercially
Abstract: An efficient synthesis of bis-nor Wieland–Miescher ke-
tone and its derivatives starting from commercially available 2-al-
lyl-2-methylcyclopenta-1,3-dione is described.
Key words: alkylation, carbocycles, cyclization, epoxidation, Wit-
tig reaction
Bicyclo[4.4.0]decanone and bicyclo[3.3.0]octanone skel-
etons are widely used in the construction of fused cyclo-
hexanoid- and cyclopentanoid-containing natural
products or their intermediates.1 Wieland–Miescher ke-
tone 1 is the most well-known representative of the former
class of compounds. Its synthesis has been thoroughly in-
vestigated and described in a non-asymmetric2 as well as
in an asymmetric way.3 The bis-nor derivative 2 of the
above mentioned ketone is also a universal building block
of the complex molecules, however, only little attention
has been paid to its synthesis and functionalization. It is
obvious that, in principle, the same synthetic route could
be exploited to obtain both synthons (Scheme 1).
available
2-allyl-2-methylcyclopenta-1,3-dione
3
(Scheme 2).
Scheme 2 Reagents and conditions: (a) NBS, H2O, acetone, 96%;
(b) Jones reagent, acetone, 90%; (c) PPh3, benzene; (d) NaI, acetone,
quant (crude); (e) K2CO3, CH2Cl2, 40 °C, 76–79%
This functionalized cyclic dione 3 is an ideal precursor for
ring annulation due to its symmetry features. Selective de-
rivatization of the double bond in 3 was the first problem
to solve. Instead of the desired epoxide, oxidation of com-
pound 3 with MCPBA led to a Baeyer–Villiger reaction
product, a d-lactone.10 However, bromohydroxylation of 3
with N-bromosuccinimide in acetone–water mixture af-
forded a bicyclic hemiacetal 4 as a ~1:1 mixture of diaste-
reoisomers in nearly quantitative yield (96%). Lack of
stereoselectivity in this step was overcome by converting
compound 4 with Jones reagent to the corresponding a-
halo ketone 5. The bromine atom in the a-position to the
carbonyl group could very easily be substituted with chlo-
ride. During the work-up procedure (washing the product
with brine) halogen exchange took place and a mixture of
bromo ketone 5a and chloro ketone 5b was obtained.
When brine was not used in the work-up, bromo ketone 5a
was obtained as a single product in 90% yield. If instead
of Jones reagent PCC was used, again a ~1:1 mixture of
halo ketones 5a and 5b was obtained.
Scheme 1
Intramolecular aldol condensation of triketone is the most
straightforward way to the targets. For Wieland–Miescher
ketone this condensation approach is the main choice in-
deed. However, synthesis of the corresponding cyclopen-
tane derivatives is a more difficult task because of their
tendency to fragmentize under basic conditions.4
Previously, in order to obtain the title compound, different
multistep procedures have been described. Among them,
in the case of monoprotected cyclopentanedione, aldol
condensation has been used. The intermediates for con-
densation were obtained via hydrolysis of nitroalkyl de-
rivatives,5 via hydration of alkynes using toxic Hg(OAc)2
6
or by microbiological reduction.7 Mori et al. synthesized
compound 2 via the ring annulation of stannyl anion gen-
The final cyclization affording bis-nor Wieland–Miescher
ketone with Wittig reagent9 was studied in more detail.
Two competitive reactions take place during the treatment
SYNTHESIS 2005, No. 18, pp 3147–3151
Advanced online publication: 16.09.2005
DOI: 10.1055/s-2005-916025; Art ID: Z08905SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

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T. Kanger et al.
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of bromo ketone 5a with Ph3P in refluxing benzene: for- avoid excess of NaBH4 because of the reduction of enone
mation of phosphonium salt 6 and reduction of bromide moiety. The stereochemistry of the obtained hydroxyl
5a affording triketone 7 (in 12–34% yield). This by-prod- group was established by NMR from the comparison of
uct can be separated from the target compound by chro- angular methyl carbon chemical shifts in 8 (18.42 ppm)
matography. It is known that reduction of a-bromo and in model 3a-methyl-1,2,3,3a,4,5-hexahydropentalene
ketones to ketones by Ph3P in nonpolar solvents is cata- (22.5 ppm).19 More than 4 ppm high field shift of methyl
lyzed by alcohols.11 The same reaction takes place also in carbon in 8 points to it cis-orientation with the vicinal OH
moist benzene.12 To avoid the formation of triketone 7, the group. The angular methyl group is most probably respon-
reaction was carried out in carefully dried benzene (dis- sible for the high selectivity.
tilled from Na) and so the amount of triketone was re-
It has been shown earlier that it is possible to alkylate bis-
nor Wieland–Miescher ketone 2 at the a-position of an
duced to 12%.13 Generation of ylide from phosphonium
salt was accomplished by the treatment of 6 with aqueous
K2CO3. Subsequent cyclization in refluxing dichlo-
romethane afforded bis-nor Wieland–Miescher ketone 2
in 79% yield (starting from 5a). Alternatively, the mixture
of bromide 5a and chloride 5b was converted to iodo ke-
tone 5c in acetone with NaI, followed by intramolecular
Wittig reaction. This procedure resulted also in the target
bicyclic compound 2, but in a considerably lower yield
(50%).
isolated carbonyl group.9a However, we found that instead
primary deprotonation of the hydroxyl group in 8 with
NaH, enolization of enone takes place. Quenching the ob-
tained dienolate with benzyl bromide affords the a-substi-
tuted product (enone 9, in 40% yield) instead of the
expected ether. Sterical hindrance in the surroundings of
the angular methyl group must be again a significant di-
rective factor that causes the unusual pathway. This find-
ing gives us an access to the compounds that are alkylated
We have recently demonstrated that 1,2-diketones are in either ring of the bis-nor Wieland–Miescher ketone 2.
valuable substrates for asymmetric oxidations affording
Enones 2 and 8 were epoxidized with H2O2 under basic
nonracemic 3-hydroxy dicarbonyl compounds,14 lactone
conditions. An investigation of the conditions that give
acids15 or spirodilactones16 in high enantiomeric purity. In
rise to heightened levels of epoxides showed that bis-nor
Wieland–Miescher ketone 2 is more sensitive to basic
conditions and nucleophilic reagents than its derivative 8
(Table 1).
connection with our ongoing project on the use of the
asymmetric oxidation in natural product synthesis17 and to
widen the synthetic scope of it, bis-nor Wieland–Miescher
ketone 2 was transformed into new 1,2-diketone deriva-
tives 12 and 13 (Scheme 3). These compounds are good
starting materials for the asymmetric oxidation giving rise
to bicyclic g-lactones known as natural products with
promising biological profile.18
Table 1 Epoxidation of Enones 2 and 8
No
1
Enone Conditions
Product (Yield%)
2
2
2
8
8
5 M NaOH, MeOH, H2O2
mixture of com-
pounds
(3 equiv), r.t., 1 h
2
3
4
5
0.1 M NaOH, MeOH, H2O2
(3 equiv), 0 °C, 3 h
10 + 10a
(in 3.5:1 ratio)
0.1 M NaOH, THF, H2O2
(2 equiv), 0 °C, 2 h
10 (58)
11 (80)
11 (52)
5 M NaOH, MeOH, H2O2
(3 equiv), r.t., 1 h
0.1 M NaOH, MeOH, H2O2
(3 equiv), r.t., 20 h
When MeOH was used as a solvent for epoxidation, the
Michael addition of the methoxy group to enone 2 took
place together with epoxidation (entry 2). Only the reac-
tion in THF afforded the target in 58% yield (entry 3). At
the same time, compound 8 was epoxidized in MeOH in
80% yield (entry 4). Strength of the base was also impor-
tant for the epoxidation reaction: a stronger base caused
the decomposition of enone 2 while it was obligatory for
enone 8 (entries 1,4,5). Formation of epoxides 10 and 11
from 2 and 8 correspondingly was stereospecific: only exo
products were formed, because endo products belong to
the highly strained trans-bicyclo[3.3.0]octane derivatives.
It is known that epoxidation of the conformationally more
Scheme 3 Reagents and conditions: (a) NaBH4, MeOH/CH2Cl2,
94%; (b) NaH, BnBr, THF, 40%; (c) 0.1 M NaOH, H2O2, THF, 58%;
(d) 5 M NaOH, H2O2, MeOH, 80%; (e) BF3·OEt2, benzene, 64%; (f)
0.01 M H2SO4, 45%
Two easily distinguished carbonyl functionalities in bis-
nor Wieland–Miescher ketone 2 allow the further deriva-
tization. Analogous to the six-membered ring Wieland–
Miescher ketone 1, the reduction of the isolated carbonyl
group in 2 is completely stereoselective affording only
cis-substituted bicycle 8 in a 94% yield. It is important to
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Synthesis of Bis-nor Wieland–Miescher Ketone
3149
MS (EI): m/z (%) = 250, 248 (M+, 10), 202 (7), 169 (5), 151 (21),
125 (29), 69 (42), 55 (68), 41 (100).
flexible Wieland–Miescher ketone 1 leads to a mixture of
exo- and endo-epoxides.20
Anal. Calcd for C9H13BrO3 (249.10): C, 43.40; H, 5.26. Found: C,
43.49; H, 5.14.
Epoxides 10 and 11 were converted into the correspond-
ing 1,2-diketones 12 and 13. Differences in the properties
of keto and hydroxy bis-nor Wieland–Miescher ketone
derivatives were also observed in the acid-catalyzed rear-
rangement step – different reaction conditions were found
necessary to rearrange keto epoxide 10 and hydroxy ep-
oxide 11. The former was rearranged with boron trifluo-
ride in 58% yield while the latter epoxide was rearranged
by refluxing in dilute sulfuric acid (0.01 M) in 45% yield
(use of boron trifluoride led to decomposition of the start-
ing epoxide).
2-(3-Bromo-2-oxopropyl)-2-methylcyclopentane-1,3-dione (5a)
To a solution of hemiacetal 4 (1.24 g, 4.99 mmol) in acetone (20
mL), was added Jones reagent (2.8 mL, 7.49 mmol) at 0 °C and the
mixture was stirred at r.t. for 24 h. i-PrOH (5 mL) was added and
the mixture was stirred for 30 min at r.t. Then the mixture was
poured into sat. aq solution of Na2SO4 (20 mL) and extracted with
EtOAc (5 × 15 mL). The combined organic phases were dried
(MgSO4) and solvent was evaporated. The residue was purified by
crystallization from EtOAc (5 mL) to afford white crystals; yield:
1.11 g (90%).
In summary, we have shown an efficient synthetic se- IR (KBr): 2996, 1716, 1390, 1080, 630 cm–1.
1H NMR (CDCl3): d = 3.85 (s, 2 H, CH2Br), 3.33 (s, 2 H, CH2CO),
quence to a valuable intermediate – bis-nor Wieland–Mi-
escher ketone 2. Its derivatization was carried out via
selective alkylation of the enone fragment or conversion
into 1,2-diketones via epoxides. The application of these
new intermediates in natural product synthesis is currently
under study.
2.92 and 2.87 (m, 4 H, H-4,5), 1.09 (s, 3 H, CH3).
13C NMR (CDCl3): d = 215.51 (C-1,3), 200.31 (COCH2Br), 52.59
(C-2), 47.35 (CH2CO), 34.63 (C-4,5), 32.42 (CH2Br), 19.59 (CH3).
MS (EI): m/z (%) = 248, 246 (M+, 2), 204 (0.5), 167 (2.5), 151 (2),
125 (90), 69 (70), 41 (100).
Anal. Calcd for C9H11BrO3 (247.09): C, 43.75; H, 4.49. Found: C,
43.88; H, 4.27.
Full assignment of 1H and 13C chemical shifts is based on the 1D and
2D FT NMR spectra on a Bruker AMX500 instrument. Solvent
peaks (CHCl3, d = 7.27, DMSO-d5, d = 2.50, CDCl3, d = 77.00,
DMSO-d6, d = 39.50) were used as chemical shift references. The
mass spectra were recorded on a Hitachi M80B spectrometer or on
Hewlett-Packard GC-MS system (HP 5988A) using electron ioniza-
tion (EI) at 70 eV. IR spectra were recorded on Perkin-Elmer Spec-
trum BX FTIR spectrometer. Elemental analyses were performed
on a Perkin-Elmer C,H,N,S-Analyzer 2400. Reactions sensitive to
oxygen or moisture were conducted under argon atmosphere in
flame-dried glassware. Commercial reagents were generally used as
received. Petroleum ether used had bp 40–60 °C.
6a-Methyl-2,3,6,6a-tetrahydropentalene-1,5-dione (2)
To a solution of bromo ketone 5a (4.03 g, 16.30 mmol) in benzene
(80 mL), was added PPh3 (8.55 g, 32.60 mmol) under argon. After
refluxing for 3 h, the mixture was cooled, diluted with CH2Cl2 (40
mL), and aq sat. solution of K2CO3 (50 mL) was added. The mixture
was stirred for 30 min, then extracted with CH2Cl2 (3 × 50 mL). The
combined organic phases were dried (MgSO4). After filtration, ben-
zene was evaporated and the residue was stirred at 40 °C for 24 h in
CH2Cl2 (100 mL). After evaporation of the solvent, the residue was
purified by column chromatography (20–40% EtOAc in petroleum
ether) affording bis-nor Wieland–Miescher ketone 2 as an oil; yield:
1.87 g (76%).
2-Bromomethyl-6a-hydroxy-3a-methylhexahydro-4H-cyclo-
penta[b]furan-4-one (4)
IR (film): 2970, 2928, 1752, 1709, 1635 cm–1.
To a solution of diketone 3 (1.1 g, 7.23 mmol) in acetone–H2O
(1:1.5, 90 mL), was added NBS (1.54 g, 8.67 mmol) at r.t. and the
mixture was stirred for 3 h. After addition of H2O (100 mL), acetone
was evaporated and the residue was extracted with EtOAc (7 × 50
mL). The combined organic phases were dried (MgSO4) and the
solvent was evaporated. The residue was purified by column chro-
matography (20% EtOAc in petroleum ether) affording a yellow oil,
as ca. 3:2 mixture of 2-endo and 2-exo isomers, which solidified in
the freezer; yield: 1.73 g (96%).
1H NMR (CDCl3): d = 5.94 (d, 1 H, J = 2.0 Hz, H-4), 3.09 and 3.02
(m, 2 H, H-3), 2.95 (ddd, 1 H, J = 2.6, 11.1, 19.1 Hz, H-2), 2.56 (d,
1 H, J = 18.0 Hz, H-6), 2.43 (td, 1 H, J = 8.9, 8.9, 19.1 Hz, H-2),
2.29 (d, 1 H, J = 18.0 Hz, H-6), 1.33 (s, 3 H, CH3).
13C NMR (CDCl3): d = 212.41 (C-1), 207.49 (C-5), 184.70 (C-3a),
126.02 (C-4), 56.67 (C-6a), 44.58 (C-6), 38.18 (C-2), 24.32 (C-3),
23.11 (CH3).
MS (EI): m/z (%) = 150 (M+, 20), 122 (53), 107 (24), 79 (100), 66
(17), 51 (30).
IR (film): 3419, 2966, 1744, 1153, 1062, 656 cm–1.
1H NMR (CDCl3): d (endo-isomer) = 4.14 (m, 1 H, H-2), 3.50 and
3.49 (m, 2 H, CH2Br), 2.53 (m, 1 H, H-3), 1.83 (dd, 1 H, J = 8.7,
13.1 Hz, H-3), 2.48 and 2.43 (m, 2 H, H-5), 2.12 and 2.38 (m, 2 H,
H-6), 1.11 (s, 3 H, CH3).
13C NMR (CDCl3): d = 219.11 (C-4), 111.73 (C-6a), 77.56 (C-2),
59.25 (C-3a), 38.80 (C-3), 37.02 (CH2Br), 35.72 (C-5), 30.44 (C-6),
15.74 (CH3).
1H NMR (CDCl3): d (exo-isomer) = 4.47 (m, 1 H, H-2), 3.31 (dd, 1
H, J = 5.2, 10.6 Hz, CH2Br), 3.28 (dd, 1 H, J = 5.8, 10.6 Hz,
CH2Br), 2.52 (m, 2 H, H-5), 2.42 and 2.06 (m, 2 H, H-6), 2.27 (dd,
1 H, J = 5.8, 13.5 Hz, H-3), 2.06 (m, 1 H, H-3), 1.12 (s, 3 H, CH3).
13C NMR (CDCl3): d = 219.29 (C-4), 112.25 (C-6a), 76.69 (C-2),
58.64 (C-3a), 39.86 (C-3), 36.11 (C-5), 34.78 (CH2Br), 30.30 (C-6),
16.23 (CH3).
Anal. Calcd for C9H10O2 (150.17): C, 71.98; H, 6.71. Found: C,
71.87; H, 6.77.
(6R*,6aR*)-6-Hydroxy-6a-methyl-4,5,6,6a-tetrahydropental-
en-2(1H)-one (8)
A solution of ketone 2 (540 mg, 3.60 mmol) in a mixture of MeOH–
CH2Cl2 (1:1, 72 mL) was cooled to 0 °C in an ice-bath and NaBH4
(34 mg, 0.90 mmol) was added. After stirring for 15 min, acetone (5
mL) was added and the mixture was allowed to warm to r.t., follow-
ing the addition of H2O (1 mL) and drying (MgSO4). Solvents were
evaporated and the residue was purified by column chromatography
(20–30% acetone in petroleum ether) affording a yellow oil; yield:
513 mg (94%).
IR (film): 3405, 2968, 1704, 1627, 1410, 1230, 1086 cm–1.
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3150
T. Kanger et al.
PAPER
1H NMR (CDCl3): d = 5.77 (dd, 1 H, J = 1.0, 2.2 Hz, H-3), 3.89 (dd,
1 H, J = 8.1, 9.5 Hz, H-6), 3.29 (br s, 1 H, OH), 2.78 and 2.53 (m, 2
H, H-4), 2.32 and 2.26 (each d, 2 H, J = 17.8 Hz, H-1), 2.23 and
2.03 (m, 2 H, H-5), 1.13 (s, 3 H, CH3).
MS (EI): m/z = 166 (M+), 138, 109, 95, 67.
Anal. Calcd for C9H10O3 (166.17): C, 65.05; H, 6.07. Found: C,
64.99; H, 6.16.
13C NMR (CDCl3): d = 210.69 (C-2), 192.32 (C-3a), 125.24 (C-3),
77.57 (C-6), 53.23 (C-6a), 49.57 (C-1), 31.85 (C-5), 23.99 (C-4),
18.42 (CH3).
(1aS*,3aS*,4R,6aS*)-4-Hydroxy-3a-methyltetrahydro-1aH-
pentaleno[1,6a-b]oxiren-2(3H)-one (11)
To a solution of enone 8 (108 mg, 0.71 mmol) in MeOH (7 mL),
was added 33% H2O2 (0.19 mL, 2.13 mmol) at r.t., followed by
dropwise addition of aq 5 M NaOH (0.035 mL, 0.18 mmol). After
stirring for 1 h, the mixture was poured into brine (10 mL) and ex-
tracted with EtOAc (5 × 10 mL). The combined organic phases were
dried (MgSO4) and evaporated. The residue was purified by column
chromatography (10% acetone in petroleum ether), to afford a yel-
low oil; yield: 95 mg (80%).
MS (EI): m/z (%) = 152 (M+, 12), 124 (63), 109 (100), 79 (71).
Anal. Calcd for C9H12O2 (152.19): C, 71.03; H, 7.95. Found: C,
70.38; H, 8.06.
(6R*,6aR*)-3-Benzyl-6-hydroxy-6a-methyl-4,5,6,6a-tetrahy-
dropentalen-2(1H)-one (9)
A suspension of NaH (9.2 mg, 0.23 mmol) in THF (3 mL) was
cooled in an ice-bath under argon. A solution of enone 8 (105 mg,
0.69 mmol) in THF (4 mL) was added dropwise and the mixture
was stirred for 30 min. A second portion of NaH (9.2 mg, 0.23
mmol) was added and after another 30 min, a third portion of NaH
(9.2 mg, 0.23 mmol) was added. The mixture was stirred for addi-
tional 30 min followed by addition of benzyl bromide (0.16 mL,
1.38 mmol). The mixture was stirred for 4 h at 0 °C and for over-
night at r.t. After addition of H2O (20 mL), the mixture was extract-
ed with EtOAc (4 × 20 mL). The combined organic phases were
dried (MgSO4) and the solvent was evaporated. The residue was pu-
rified by column chromatography (10% EtOAc in petroleum ether)
affording a yellow oil; yield: 67 mg (40%).
IR (film): 3419, 2970, 1743, 1248, 1097, 1070, 1048, 883 cm–1.
1H NMR (CDCl3): d = 3.88 (t, 1 H, J = 8.5 Hz, H-4), 3.21 (s, 1 H,
H-1), 2.37 (d, 1 H, J = 19.0 Hz, H-3), 2.33 (m, 1 H, H-6), 2.27 (m,
1 H, H-5), 2.18 (br s, 1 H, OH), 2.04 (d, 1 H, J = 19.0 Hz, H-3), 1.88
(m, 2 H, H-5,6), 1.13 (s, 3 H, CH3).
13C NMR (CDCl3): d = 209.47 (C-2), 75.98 (C-4), 75.80 (C-6a),
62.77 (C-1), 44.98 (C-3a), 44.84 (C-3), 29.65 (C-5), 20.93 (C-6),
13.28 (CH3).
MS (EI): m/z = 168 (M+), 139, 124, 95, 69.
(3aR*,6aR*)-5-Hydroxy-6a-methyl-2,3,3a,6a-tetrahydropen-
talene-1,4-dione (12)
IR (film): 3411, 3028, 2966, 1698, 1652, 1603, 1495, 1083, 1041,
705 cm–1.
To a solution of epoxide 10 (53 mg, 0.32 mmol) in benzene (5 mL),
was added BF3·OEt2 (40 mL, 0.32 mmol). The resulting mixture was
refluxed for 2 h. After addition of aq sat. NaHCO3 solution (10 mL),
the mixture was extracted with EtOAc (6 × 5 mL), and the com-
bined organic layers were dried (MgSO4) and evaporated. The resi-
due was purified by column chromatography (20% acetone in
petroleum ether) to give 12; yield: 34 mg (64%).
1H NMR (CDCl3): d = 7.28 (t, 2 H, J = 7.4 Hz, meta-Harom), 7.21 (t,
1 H, J = 7.4 Hz, para-Harom), 7.18 (d, 2 H, J = 7.4 Hz, ortho-Harom),
3.89 (dd, 1 H, J = 8.1, 9.5 Hz, H-6), 3.56 (d, 1 H, J = 15.3 Hz,
PhCH2), 3.43 (dd, 1 H, J = 1.1, 15.3 Hz, PhCH2), 2.54 (m, 1 H, H-
4), 2.37 and 2.34 (d each, 2 H, J = 17.7 Hz, H-1), 2.35 (br s, 1 H,
OH), 2.33 (m, 1 H, H-4), 2.22 and 2.00 (m each, 2H, H-5), 1.15 (s,
3 H, CH3).
13C NMR (CDCl3): d = 209.11 (C-2), 184.62 (C-3a), 138.81 (Carom),
135.83 (C-3), 128.55 (o-CHarom), 128.41 (m-CHarom), 126.11 (p-
CHarom), 78.10 (C-6), 51.14 (C-6a), 48.99 (C-1), 32.11 (C-5), 29.63
(PhCH2), 22.93 (C-4), 18.66 (CH3).
IR (KBr): 3151, 2974, 2932, 1739, 1690, 1608 cm–1.
1H NMR (CDCl3): d = 6.32 (s, 1 H, H-6), 2.73 (m, 1 H, H-3a), 2.43
and 2.25 (m, 2 H, H-2), 2.14 and 2.15 (m, 2 H, H-3), 1.13 (s, 3 H,
CH3).
1H NMR (DMSO-d6): d = 9.99 (s, 1 H, OH), 6.13 (s, 1 H, H-6), 2.68
(d, 1 H, J = 8.7 Hz, H-3a), 2.41 and 1.90 (m, 2 H, H-2), 2.11 and
2.10 (m, 2 H, H-3), 1.23 (s, 3 H, CH3).
MS (EI): m/z = 242 (M+), 214, 196, 181, 91, 77.
Anal. Calcd for C16H18O2 (242.31): C, 79.31; H, 7.49. Found: C,
78.81; H, 7.55.
13C NMR (CDCl3): d = 215.67 (C-1), 205.41 (C-4), 153.21 (C-5),
132.32 (C-6), 52.49 (C-3a), 51.76 (C-6a), 35.20 (C-2), 20.15 (C-3),
19.62 (CH3).
13C NMR (DMSO-d6): d = 216.49 (C-1), 204.89 (C-4), 154.56 (C-
5), 131.40 (C-6), 52.21 (C-3a), 50.84 (C-6a), 34.90 (C-2), 19.78 (C-
3), 19.66 (CH3).
(1aS*,3aR*,6aS*)-3a-Methyltetrahydro-1aH-pentaleno[1,6a-
b]oxirene-2,4-dione (10)
To a solution of enone 2 (1.46 g, 9.74 mmol) in THF (50 mL), was
added a solution of H2O2 (33% in H2O, 1.77 mL, 19.47 mmol) at
0 °C, followed by dropwise addition of 0.1 M NaOH (48.70 mL,
4.87 mmol). After stirring for 2 h, the mixture was poured into a so-
lution of brine (100 mL) and extracted with EtOAc (5 × 50 mL). The
combined organic phase were dried (MgSO4) and evaporated. The
residue was purified by column chromatography (10% acetone in
petroleum ether), affording the target compound as white crystals;
yield: 938 mg (58%).
MS (EI): m/z = 166 (M+), 138, 120, 110, 95.
Anal. Calcd for C9H10O3 (166.17): C, 65.05; H, 6.07. Found: C,
65.01; H, 6.10.
(3aR*,4R*,6aR*)-2,4-Dihydroxy-3a-methyl-4,5,6,6a-tetrahy-
dropentalen-1(3aH)-one (13)
A mixture of epoxide 11 (40 mg, 0.24 mmol) and 0.01 M H2SO4
(5.5 mL) was heated at 100 °C for 24 h. The mixture was cooled and
extracted with EtOAc (4 × 5 ml). The EtOAc extract was dried
(MgSO4) and evaporated. The residue was purified by column chro-
matography (25% acetone in petroleum ether), affording a yellow
solid; yield: 18 mg (45%).
IR (KBr): 3066, 2944, 2924, 1753, 1735, 1125, 1057, 1002 cm–1.
1H NMR (CDCl3): d = 3.34 (s, 1 H, H-1), 2.88 (ddd, 1 H, J = 1.9,
10.5, 19.4 Hz, H-5), 2.69 (ddd, 1 H, J = 9.6, 10.5, 13.6 Hz, H-6),
2.67 (d, 1 H, J = 19.7 Hz, H-3), 2.52 (ddd, 1 H, J = 9.5, 9.6, 19.4 Hz,
H-5), 2.17 (ddd, 1 H, J = 1.9, 9.5, 13.6 Hz, H-6), 2.10 (d, 1 H,
J = 19.7 Hz, H-3), 1.25 (s, 3 H, CH3).
13C NMR (CDCl3): d = 213.91 (C-4), 206.36 (C-2), 75.41 (C-6a),
61.84 (C-1), 48.74 (C-3a), 42.69 (C-3), 36.72 (C-5), 21.04 (C-6),
16.85 (CH3).
IR (KBr): 3417, 3108, 2963, 2932, 1695, 1649, 1422, 1220, 1103,
966 cm–1.
Synthesis 2005, No. 18, 3147–3151 © Thieme Stuttgart · New York

PAPER
Synthesis of Bis-nor Wieland–Miescher Ketone
3151
1H NMR (CDCl3 + CD3OD): d = 6.29 (s, 1 H, H-3), 3.87 (m, 1 H,
H-4), 2.38 (d, 1 H, J = 10.1 Hz, H-6a), 2.22 and 1.67 (m, 2 H, H-6),
1.64 (m, 2 H, H-5), 1.26 (s, 3 H, CH3).
13C NMR (CDCl3 + CD3OD): d = 207.68 (C-1), 152.35 (C-2),
137.50 (C-3), 76.34 (C-4), 54.74 (C-6a), 51.43 (C-3a), 32.73 (C-5),
26.43 (C-6), 19.73 (CH3).
(6) Geetha, G.; Raju, N.; Rajagopalan, K.; Swaminathan, S.
Indian J. Chem. 1981, 20B, 238.
(7) Brooks, D. W.; Woods, K. W. J. Org. Chem. 1987, 52, 2036.
(8) (a) Kinoshita, A.; Mori, M. Chem. Lett. 1994, 1475.
(b) Mori, M.; Isono, ; Kaneta, N.; Shibasaki, M. J. Org.
Chem. 1993, 58, 2972.
(9) (a) Trost, B. M.; Curran, D. P. J. Am. Chem. Soc. 1980, 102,
5699. (b) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981,
22, 4929.
MS (EI): m/z = 168 (M+), 150, 122, 97, 79.
(10) 6-Allyl-6-methyldihydro-2H-pyran-2,5 (6H)-dione: 1H
NMR (CDCl3): d = 5.72 (m, 1 H, =CH), 5.13 and 5.15 (m, 2
H, =CH2), 2.84 and 2.88 (m, 2 H, H-3), 2.73 and 2.60 (m, 2
H, H-4), 2.65 and 2.45 (tdd each, 2 H, J = 0.9, 0.9, 7.4, 14.1
Hz, CH2CH=CH2), 1.48 (s, 3 H, CH3). 13C NMR (CDCl3):
d = 207.23 (C-5), 169.24 (C-2), 130.35 (=CH), 121.06
(=CH2), 88.71 (C-6), 43.20 (CH2CH=CH2), 33.96 (C-4),
28.04 (C-3), 24.92 (CH3).
(11) Borowitz, I. J.; Parnes, H.; Lord, E.; Yee, K. C. J. Am. Chem.
Soc. 1972, 94, 6817.
(12) Borowitz, I. J.; Grossman, L. J. Tetrahedron Lett. 1962, 471.
(13) Alternatively, a crystalline phosphonium salt can be isolated
by filtration remaining by-product into solution. However,
this isolation decreases the overall yield of compound 2 from
79% to 64%.
Acknowledgment
The authors thank Estonian Science Foundation for financial sup-
port (grant numbers 4976, 5628 and 5133) and Mrs Tiiu Kailas for
IR and elemental analyses.
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Synthesis 2005, No. 18, 3147–3151 © Thieme Stuttgart · New York