A convenient route to 1-(2-oxiranyl)-1,4-diketones and their application to the synthesis of endo-brevicomin, endo-isobrevicomin, frontalin and related compounds via alkylated 6,8-dioxabicyclo[3.2.1]octan-2-ones

Article abstract of DOI:10.1016/j.tet.2003.12.027

1-(2-Oxiranyl)-1,4-alkanediones were prepared from the ethylene acetals of ethyl 4-oxoalkanoates via the oxidation of the intermediate 1,2- dialkylcyclopropanols having a protected carbonyl group in an aliphatic chain. Intramolecular acetalization of these epoxy dicarbonyl compounds gave alkylated 6,8-dioxabicyclo[3.2.1]octan-2-ones in good yields. The latter were found suitable to be precursors for (±)-endo-brevicomin and its 2-hydroxy derivative, as well as (±)-endo-isobrevicomin and (±)-frontalin.

Full text of DOI:10.1016/j.tet.2003.12.027

Tetrahedron 60 (2004) 1473–1479
A convenient route to 1-(2-oxiranyl)-1,4-diketones and their
application to the synthesis of endo-brevicomin,
endo-isobrevicomin, frontalin and related compounds via
alkylated 6,8-dioxabicyclo[3.2.1]octan-2-ones
*
Vladimir I. Tyvorskii, Dmitry A. Astashko and Oleg G. Kulinkovich
Department of Organic Chemistry, Belarusian State University, Fr. Scorina Avenue, 4, 220050 Minsk, Belarus
Received 10 September 2003; revised 13 November 2003; accepted 11 December 2003
Abstract—1-(2-Oxiranyl)-1,4-alkanediones were prepared from the ethylene acetals of ethyl 4-oxoalkanoates via the oxidation of the
intermediate 1,2-dialkylcyclopropanols having a protected carbonyl group in an aliphatic chain. Intramolecular acetalization of these epoxy
dicarbonyl compounds gave alkylated 6,8-dioxabicyclo[3.2.1]octan-2-ones in good yields. The latter were found suitable to be precursors for
(^)-endo-brevicomin and its 2-hydroxy derivative, as well as (^)-endo-isobrevicomin and (^)-frontalin.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
beetles, Dendroctonus ponderosae. Frontalin 1e is the
aggregation pheromone of southern pine bark beetle,
Dendroctonus frontalis.4
Alkylated 6,8-dioxabicyclo[3.2.1]octanes play an important
role in systems of chemical communication among many
bark beetles, which infect pine trees.1 Brevicomin is a
typical pheromone component of Dendroctonus and
Dryocoetes pine beetles, and it is frequently produced by
these insects as a mixture of exo- and endo-diastereomers at
C-7 (1a and 1b, Fig. 1), with a large excess of the (þ)-exo-
brevicomin 1a.1,2 In contrast to the latter, the enantiomeric
excess in the accompanying endo-brevicomin 1b is rarely
greater than 70%.1,2c–e Both the exo- and endo-isomers of
isobrevicomin (1c and 1d, respectively) were isolated in
1996 by Francke and co-workers3 as the minor components
of the volatiles, obtained from male mountain pine bark
Compounds 1a–e all have been the target of numerous
syntheses in both racemic and enantiomerically pure
form.1,5,6 The general strategy of these syntheses is the
generation of an appropriate 5,6-epoxyketones or corre-
sponding dihydroxyketone, followed by intramolecular
acetalization.1,3,7 Using the deuterated and 18O-labeled
(Z)-6-nonen-2-one, Vanderwel and Oehlschlager found that
this unsaturated ketone serves as a precursor of (þ)-exo-
brevicomin 1a in the bark beetles D. ponderosae Hopkins
and that the pheromone biosynthesis proceeds through a cis-
epoxyketone intermediate, without its conversion to a diol
prior to the cyclization stage.8 For the formation of endo-
isomers 1b and 1d, the corresponding trans-epoxides are
required.1,7a For example, racemic endo-isobrevicomin 1d
has been synthesized from the epoxide of (E)-7-nonen-3-
one.3
Recently, we have reported a flexible and convenient
method for the preparation of aliphatic a,b-epoxyketones
based on a manganese-catalyzed ring cleavage of
1-substituted and 1,2-disubstituted cyclopropanols with
gaseous oxygen followed by transformation of the hydro-
peroxyketone intermediates into the target products, under
the action of potassium hydroxide.9 The simplicity of this
one-pot procedure, coupled with facile availability of the
corresponding cyclopropanols,10,11 makes it attractive for
the synthesis of epoxyketones bearing an additional
functional group in the aliphatic chain. In the present
Figure 1.
Keywords: Cyclopropanols; Oxidation; Oxiranes; 1,4-Dicarbonyl
compounds; Pheromones.
*
Corresponding author. Tel.: þ375-17-2095459; fax: þ375-17-2265609;
e-mail address: tyvorskii@bsu.by
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.027

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V. I. Tyvorskii et al. / Tetrahedron 60 (2004) 1473–1479
work, we wish to describe the application of this
methodology to the preparation of 1-(2-oxiranyl)-1,4-
diketones 6, which are then employed in the synthesis of
6,8-dioxabicyclo[3.2.1]octane derivatives, including (^)-
endo-brevicomin 1b, (^)-endo-isobrevicomin 1d, (^)-
frontalin 1e and the related hydroxy compounds 8a, 9a.
formation of a ca. 1:1 mixture of two products, an expected
cyclic ketone 7a and epoxy diketone 6a. Furthermore, it was
proven that no transformation 6a!7a took place during this
catalytic process. Therefore, for the preparation of
compounds 7a–c, the two-step procedure including depro-
tection of ketals 4a–c with diluted H2SO4 on SiO2 followed
by cyclization of obtained 1-(2-oxiranyl)-1,4-diketones
6a–c under the action of boron trifluoride etherate was
found to be more effective (Scheme 1, steps v–vi, 62–82%
overall yield of 7a–c from 4a–c). The intramolecular
reaction of the trans-oxirane moiety with the remote
carbonyl group in precursors 6a,b proceeded with high
stereoselectivity, the bicyclic endo-acetals 7a,b being
the single isolated products. The relative configuration
of compounds 7a,b was confirmed by comparison of
their spectral data with that reported for 7a and its exo-
isomer,14 as well as by subsequent synthetic
transformations.
2. Results and discussion
Epoxyketones 4a,b, with an additional protected carbonyl
group, have been obtained in two preparative steps in an
overall yield of 60–76%, starting from ethylene acetals of
ethyl 4-oxoalkanoates 2a,b, via the cyclopropanols 3a,b, as
a key intermediates (Scheme 1). The latter were prepared by
cyclopropanation of esters 2a,b with butylmagnesium
bromide and propylmagnesium bromide, respectively, in
the presence of Ti(IV) isopropoxide.10 This reaction
1
proceeded with high diastereoselectivity (de.94% by H
Bicyclic ketones 7a–c have been converted to the racemic
endo-brevicomin 1b, endo-isobrevicomin 1d, and frontalin
1e, respectively, by a conventional deoxygenation method,
which was earlier described for the preparation of
compounds (^)-1b14 and (þ)-1e.15 Each particular ketone
7 was treated with ethanedithiol in the presence of BF3·OEt2
and the resulting cyclic dithioketals were reduced with
Raney nickel to furnish the target pheromones. Several
other methods known to effect the deoxygenation of ketones
or secondary alcohols were tried, but the Wolff–Kishner
reaction of ketone 7a, the reduction of its tosylhydrazone as
well as the reduction of mesylate or xanthogenate of alcohol
8a, failed to give only a trace amount of the desired product.
NMR spectroscopy). The relative stereochemistry of 1,2-
disubstituted cyclopropanols 3a,b was assigned to be cis on
the basis of literature data.11 The Mn(II) abietate catalyzed
oxidative cleavage of compounds 3a,b with molecular
oxygen, followed by treatment of the reaction mixture with
aqueous potassium hydroxide, led to the expected products
4a,b, wich exhibit a trans-configuration of the oxirane ring.9
The synthesis of compound 4c started with the cyclo-
propanol 3c, prepared from the protected ethyl levulinate 2a
and propylmagnesium bromide. Compound 3c was sub-
jected to the reaction with the bromine–pyridine complex,
followed by dehydrobromination of resulting b-bromo-
ketone.12 The corresponding a,b-unsaturated ketone thus
formed was epoxidized without isolation by the action of
alkaline hydrogen peroxide13 to give 4c in 60% overall yield
from 2a (Scheme 1; steps i, iii, iv).
Compounds 7a–c are potentially suitable starting materials
for the synthesis of 2-hydroxylated 6,8-dioxa-
bicyclo[3.2.1]octanes, especially because several isomeric
hydroxybrevicomins have been produced by male mountain
pine beetles, D. ponderosae.1,3 As anticipated, the reduction
of ketone 7a in an etheral solution, with a slight excess of
lithium aluminum hydride, followed by careful addition of
Attempted transacetalization of compound 4a into the
desired 6,8dioxabicyclo[3.2.1]octan-2-one 7a, by treatment
with 10% aq. H2SO4 in diethyl ether, resulted in the
Scheme 1. Reagents: (i) 4 equiv. R2CH2CH2MgBr, 20 mol% Ti(Oi-Pr)4, Et2O/THF (2:3); (ii) O2, 1 mol% Mn(II) abietate, PhH, then KOH, H2O; (iii) Br2/Py.
Et2O, then Al2O3, n-C5H12; (iv) H2O2, i-PrOH, NaOH; (v) 15% aq. H2SO4/SiO2, CH2Cl2; (vi) BF3·OEt2, CH2Cl2; (vii) HSCH2CH2SH, BF3·OEt2, CH2Cl2;
(viii) Ni(Ra), EtOH.

V. I. Tyvorskii et al. / Tetrahedron 60 (2004) 1473–1479
1475
Scheme 2. Reagents: (i) 0.75 equiv. LiAlH4, Et2O; then 5% HCl; (ii) p-TsOH, benzene; (iii) NaH, THF; then MsCl; (iv) MsCl, Et3N, Et2O.
diluted hydrochloric acid (to pH¼7–8), afforded the new
2-hydroxy-endo-brevicomin 8a in almost quantitative yield
and with a de.95% (Scheme 2). Similarly, reduction of 7a
with (t-BuO)3LiAlH or with sodium metal in isopropyl
alcohol gave the same compound 8a, containing an
equatorial OH group. The formation of 8a is probably due
to steric hindrance imposed by the endo-arranged 7-Et
group for equatorial attack on the ketone 7a with the
reducing reagent.
mesylate 8b is the large coupling constant of 10.9 Hz
between the axial protons at C-3 and at C-2, thus indicating
the equatorial position of the OH group in precursor
compound 8a. Additionally, the coupling constant of
3.9 Hz between protons at C-1 and C-7 is in a good
agreement with the reported data for related endo-bicyclic
acetals, as this value differs appreciably from J1,7,1 Hz
observed for known exo-isomers of 8a.3
In conclusion, we have developed effective methods for the
preparation of 1-(2-oxiranyl)-1,4-diketones which were
easily converted into alkylated 6,8-dioxabicyclo[3.2.1]-
octan-2-ones. The latter are versatile precusors of various
pheromone components, including racemic endo-brevi-
comin, endo-isobrevicomin and frontalin, as well as the
unknown 2-hydroxylated endo-brevicomin.
Remarkably, the single compound 9a, containing 2,8-
dioxabicyclo[3.2.1]octane sceleton, was isolated in 95%
yield by the reduction of ketone 7a with LiAlH4 followed by
quenching with an excess of aqueous HCl. Compound 9a
was earlier identified by Francke’s group3 as a minor
volatile component from D. ponderosae males. The
reduction of ketone 7a with NaBH4 in methanol resulted
in the formation of a mixture of isomers 8a and 9a in the
ratio of 1:1. We found, that 2-hydroxy-endo-brevicomin 8a
is extremely sensitive to acids, including Lewis acids. Thus,
compound 8a rearranges completely after ca. 3 h to its
isomer 9a in a benzene solution, in the presence of a trace
amount of p-TsOH at room temperature. This is consistent
with the observations of Francke,3 who was first to suggest
that the lability of compound 8a is a possible explanation
of its lack among three other natural diastereomeric
2-hydroxylated brevicomins in D. ponderosae. The
synthesis of compound 8a involving an acid-catalyzed
ring-closing stage was undertaken by Barbas III, Lerner and
co-workers,16 however, the presented spectral data clearly
demonstrate that the product 9a was isolated instead of the
desired and mistakenly reported compound 8a.
3. Experimental
IR spectra were measured on a Specord 75 IR or FT-IR
1
Perkin–Elmer 1000 spectrophotometer. H NMR spectra
were recorded at 400 MHz (Bruker Avance 400) with
CDCl3 or C6D6 as a solvent. 13C NMR spectra were
recorded with a Bruker Avance 400 at 100.6 MHz with
CDCl3 or C6D6 as a solvent. Mass spectra were obtained on
a Shimadzu QP-5000 GC/MS spectrometer. Melting points
were determined in open capillaries and are uncorrected.
Preparative column chromatography was carried out on
silica gel (Merck; 70–230 mesh). All chemicals were
reagent grade; solvents were dried and distilled prior to use.
Ethyl 3-(2-ethyl-1,3-dioxolan-2-yl)propanoate 2b was
prepared by standard acetalization procedure from ethyl
4-oxohexanoate.17,18
The structure of compound 8a was confirmed by 1H NMR,
13C NMR and mass spectroscopy, however more evident
data on the relative stereochemistry of 8a have been
corroborated by spectral characteristics of its mesylate 8b.
Surprisingly, the reaction of 8a with mesyl chloride in the
presence of Et3N under standard conditions afforded
mesylate 9b of isomeric alcohol 9a. This may be due to
the rearrangement of starting 8a or its mesylate 8b under the
action of nascent HCl (or Et3NHþCl2). The mesylate 8b
was prepared by standard treatment of 8a with NaH and
reaction of the subsequent sodium alkoxide with MsCl.
3.1. 2-Alkyl-1-[2-(2-alkyl-1,3-dioxolan-2-yl)ethyl]-1-
cyclopropanols (3a–c). General procedure
A solution of propyl- or butylmagnesium bromide
(35 mmol) in a mixture of THF (8 mL) and diethyl ether
(10 mL) was slowly added to a stirred solution of 10 mmol
of corresponding ethyl 3-(2-alkyl-1,3-dioxolan-2-yl)-
propanoate 2a,b and Ti(Oi-Pr)4 (0.6 mL, 2 mmol) in THF
(12 mL) at room temperature. The mixture was stirred for
2 h, treated with saturated solution of ammonium chloride,
1
The distinctive characteristic of the H NMR spectrum of

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V. I. Tyvorskii et al. / Tetrahedron 60 (2004) 1473–1479
filtered and extracted with ether (3£20 mL). Etheral extracts
were washed with brine and dried (Na2SO4). The products
were isolated by distillation under reduced pressure.
3.21 (d, J¼1.6 Hz, 1H); 3.85–3.94 (m, 4H). 13C NMR
(100.6 MHz, CDCl3): d 9.4, 23.8, 24.8, 31.6, 32.3, 59.3,
64.55, 64.61, 109.0, 128.2, 207.1. Anal. calcd for C10H18O3:
C, 61.66; H, 8.47. Found: C, 61.84; H, 8.29.
3.1.1. 2-Ethyl-1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1-
cyclopropanol (3a). Yield: 1.8 g (90%); colourless liquid;
bp 93–95 8C/1 Torr. IR (CCl4): n 3440, 3066, 2907, 2840,
1440, 1373, 1200, 1053 cm21. 1H NMR (400 MHz, CDCl3):
d 20.03 (t, J¼5.2 Hz, 1H); 0.73 (dd, J¼9.6, 5.2 Hz, 1H);
0.82–0.92 (m, 1H); 0.93 (t, J¼7.2 Hz, 3H); 0.99–1.12 (m,
1H); 1.32 (s, 3H); 1.33–1.45 (m, 1H); 1.52–1.62 (m, 1H);
1.64–1.76 (m, 1H); 1.89 (t, J¼7.4 Hz, 2H); 3.45 (br. s, 1H);
3.88–3.96 (m, 4H). 13C NMR (100.6 MHz, CDCl3): d 13.9,
19.1, 22.7, 23.5, 27.6, 28.3, 35.6, 58.6, 64.42, 64.45, 110.1.
Anal. calcd for C11H20O3: C, 65.97; H, 10.07. Found: C,
65.77; H, 9.87.
3.2.2. trans-3-(2-Ethyl-1,3-dioxolan-2-yl)-1-(3-methyl-2-
oxiranyl)-1-propanone (4b). Yield: 1.63 g (76%); colour-
less liquid; bp 115–117 8C/4 Torr. IR (film): n 2970, 2883,
1714, 1464, 1422, 1306, 1204, 1141, 1067, 950, 897, 842,
769 cm21
.
1H NMR (400 MHz, CDCl3): d 0.86 (t,
J¼7.6 Hz, 3H); 1.36 (d, J¼4.8 Hz, 3H); 1.57 (q,
J¼7.6 Hz, 2H); 1.84–1.98 (m, 2H); 2.28 (ddd, J¼17.6,
8.4, 6.4 Hz, 1H); 2.45 (ddd, J¼17.6, 8.2, 6.8 Hz, 1H); 3.1
(qd, J¼4.8, 1.6 Hz, 1H); 3.15 (d, J¼1.6 Hz, 1H); 3.88 (s,
4H). 13C NMR (100.6 MHz, CDCl3): d 7.9, 17.4, 29.8, 29.9,
31.6, 54.1, 60.5, 64.8, 64.9, 111.0, 207.1. Anal. calcd for
C11H18O4: C, 61.66; H, 8.47. Found: C, 61.68; H, 8.41.
3.1.2. 1-[2-(2-Ethyl-1,3-dioxolan-2-yl)ethyl]-2-methyl-1-
cyclopropanol (3b). Yield: 1.56 g (78%); colourless liquid;
bp 107–109 8C/3 Torr. IR (CCl4): n 3451, 3076, 2912,
3.2.3. Preparation of 3-(2-methyl-1,3-dioxolan-2-yl)-1-
(2-methyl-2-oxiranyl)-1-propanone (4c). Bromine–pyri-
dine complex (2.38 g, 10 mmol) was added slowly to a
stirred solution of cyclopropanol 3c (1.86 g, 10 mmol) in
dry Et2O (25 mL) at 0 8C. The reaction mixture was stirred
at room temperature for 1 h, filtered through a short pad of
alumina and the solvent was evaporated. The residue was
dissolved in pentane (30 mL) and stirred with Al2O3 (10 g)
for 12 h. The reaction mixture was filtered, Al2O3 was
washed with ether and the solvent was evaporated to give
2-methyl-5-(2-methyl-1,3-dioxolan-2-yl)-1-penten-3-one
(5). This compound 5 was used for further transformations
without purification (purity .95%; 1H NMR spectroscopy).
Yield: 1.73 g (94%); colourless liquid. IR (CCl4): n 3093,
1
2853, 1438, 1363, 1219, 1048 cm21. H NMR (400 MHz,
CDCl3): d 20.04–0.02 (m, 1H); 0.75–0.82 (m, 1H); 0.85–
0.94 (m, 4H); 1.01 (s, 3H); 1.60–1.70 (m, 4H); 1.85–1.91
(m, 2H); 2.93 (br. s, 1H) 3.9–3.98 (m, 4H). 13C NMR
(100.6 MHz, CDCl3): d 8.0, 14.1, 19.6, 20.6, 28.0, 29.6,
33.0, 58.5, 64.8, 64.9, 112.1. Anal. calcd for C11H20O3: C,
65.97; H, 10.07. Found: C, 66.11; H, 9.89.
3.1.3. 2-Methyl-1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-
1-cyclopropanol (3c). Yield: 1.48 g (80%); colourless
liquid; bp 92–93 8C/2 Torr. IR (CCl4): n 3467, 3053,
1
2947, 2893, 1467, 1387, 1053 cm21. H NMR (400 MHz,
1
CDCl3): d 20.05–0 (m, 1H); 0.74–0.8 (m, 1H); 0.88 (dd,
J¼6.8, 2.0 Hz, 1H); 0.99 (d, J¼1.6 Hz, 3H); 1.33 (s, 3H);
1.61–1.67 (m, 2H); 1.87–1.93 (m, 2H); 2.92 (br. s, 1H);
3.93–3.97 (m, 4H). 13C NMR (100.6 MHz, CDCl3): d 14.1,
19.5, 20.5, 23.6, 28.2, 35.6, 58.4, 64.4, 64.5, 110.1. Anal.
calcd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.56; H,
9.57.
2933, 2867, 1680, 1440, 1373, 1320, 1053, 933 cm21. H
NMR (400 MHz, CDCl3): d 1.31 (s, 3H); 1.85 (s, 3H); 1.99
(t, J¼7.8 Hz, 2H); 2.76 (t, J¼7.8 Hz, 2H); 3.86–3.97 (m,
4H); 5.74 (s, 1H); 5.95 (s, 1H). 13C NMR (100.6 MHz,
CDCl3): d 17.7, 23.9, 32.0, 33.34, 64.6, 109.4, 124.2, 128.4.
(The signal due to carbonyl group is not observed in the
200 ppm region). Anal. calcd for C10H16O3: C, 65.19; H,
8.75. Found: C, 65.01; H, 8.52.
3.2. trans-3-(2-Alkyl-1,3-dioxolan-2-yl)-1-(3-alkyl-2-
oxiranyl)-1-propanones (4a,b). General procedure
To a stirred solution of this material (1.73 g, 9.4 mmol) and
NaOH (0.5 g) in a mixture of iPrOH (12 mL) and H2O
(7 mL) was added 30% H2O2 (5 mL, 50 mmol) at 0 8C. The
reaction mixture was stirred at 0 8C for 3 h, diluted with
brine (25 mL) and extracted with CH2Cl2 (3£15 mL). The
combined organic phases were washed with brine and dried
(Na2SO4). The solvent was removed and the crude epoxide
4c was purified by column chromatography (silica gel,
EtOAc–cyclohexane, 1:5). Yield: 1.5 g (80%); colourless
liquid. IR (CCl4): n 2920, 2853, 1707, 1440, 1373, 1133,
A solution of corresponding cyclopropanol 3a,c (10 mmol)
and Mn(II) abietate (0.1 g, 1 mol%) in dry benzene (60 mL)
was stirred under oxygen atmosphere at room temperature
for 3–5 h. Then aq KOH (0.5 M, 5 mL) was added and the
mixture was vigorously stirred at room temperature for
1–2 h. After filtration, the organic layer was separated and
the aqueous solution was extracted with benzene (3£5 mL).
The combined organic phases were washed with brine and
dried (Na2SO4). The solvent was removed and the crude
epoxides 3a–g were purified by distillation under reduced
pressure.
1
1053 cm21. H NMR (400 MHz, CDCl3): d 1.28 (s, 3H);
1.48 (s, 3H); 1.86–2.02 (m, 2H); 2.25 (ddd, J¼17.6, 8.4,
6.4 Hz, 1H); 2.51 (ddd, J¼17.6, 8.5, 6.4 Hz, 1H); 2.82 (d,
J¼5.2 Hz, 1H); 2.96 (d, J¼5.2 Hz, 1H); 3.86–3.96 (m, 4H).
13C NMR (100.6 MHz, CDCl3): d 16.6, 23.8, 29.5, 32.5,
51.9, 59.5, 64.46, 64.55, 109.1, 208.9. Anal. calcd for
C10H16O4: C, 59.99; H, 8.05. Found: C, 60.11; H, 8.19.
3.2.1. trans-1-(3-Ethyl-2-oxiranyl)-3-(2-methyl-1,3-
dioxolan-2-yl)-1-propanone (4a). Yield: 1.82 g (85%);
colourless liquid; bp 93–95 8C/1 Torr. IR (film): n 2977,
2881, 1711, 1436, 1378, 1223, 1131, 1053, 949, 920,
858 cm21
.
1H NMR (400 MHz, CDCl3): d 0.99 (t,
3.3. 1-(2-Oxiranyl)-1,4-alkanediones (6a–c). General
procedure
J¼7.6 Hz, 3H); 1.28 (s, 3H); 1.57–1.71 (m, 2H); 1.89–
2.03 (m, 2H); 2.33 (ddd, J¼17.4, 8.2, 6.4 Hz, 1H); 2.50
(ddd, J¼17.4, 8.3, 6.4 Hz, 1H); 3.03 (td, J¼5.3, 1.6 Hz, 1H);
To a stirred suspension of silica gel (18 g) in CH2Cl2

V. I. Tyvorskii et al. / Tetrahedron 60 (2004) 1473–1479
1477
(50 mL) was added 15% H2SO4 (1.7 g) followed by
protected compound 4a–c (10 mmol). The resulting
mixture was allowed to stir at room temperature for
5–7 h, filtered and the solvent was evaporated, affording
the crude diketones 6a–c which were purified by
column chromatography (silica gel, EtOAc–cyclohexane,
1:5).
80.1, 83.3, 107.4, 205.3. Anal. calcd for C9H14O3: C, 63.51;
H, 8.29. Found: C, 63.32; H, 8.39.
3.4.2. endo-5-Ethyl-7-methyl-6,8-dioxabicyclo[3.2.1]-
octan-2-one (7b). Yield: 1.33 g (78%); colourless liquid;
bp 94–96 8C/14 Torr. IR (CCl4): n 2995, 2947, 2880, 1735,
1
1493, 1467, 1387, 1200, 1120, 1080, 933 cm21. H NMR
(400 MHz, CDCl3): d 0.95 (t, J¼7.4 Hz, 3H); 1.14 (d,
J¼6.4 Hz, 3H); 1.78 (qd, J¼7.4, 2.4 Hz, 2H); 1.9–2.07 (m,
2H); 2.30 (td, J¼18.4, 8.0 Hz, 1H); 2.46 (ddd, J¼18.4, 8.4,
3.2 Hz, 1H); 4.13 (qd, J¼6.0, 4.8 Hz, 1H); 4.18 (d,
J¼4.8 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d 7.2,
14.1, 30.2, 32.6, 33.4, 74.4, 83.9, 109.1, 206.0. MS (70 eV)
m/z (%): 170 (0.2), 149 (5), 116 (1), 113 (2), 87 (1), 86 (2),
75 (4), 74 (100), 73 (1), 72 (1), 71 (1), 70 (1), 69 (2), 60 (23),
58 (2), 57 (13), 56 (63), 55 (4), 54 (2), 46 (7), 45 (66), 44
(14), 43 (57), 42 (24), 41 (11), 40 (2), 39 (2). Anal. calcd for
C9H14O3: C, 63.51; H, 8.29. Found: C, 63.64; H, 8.19.
3.3.1. trans-1-(3-Ethyl-2-oxiranyl)-1,4-pentanedione
(6a). Yield: 1.63 g (96%); colourless liquid. IR (film): n
2972, 2923, 2881, 1712, 1465, 1431, 1403, 1362, 1233,
1163, 1103, 919, 861 cm21. 1H NMR (400 MHz, CDCl3): d
0.98 (t, J¼7.6 Hz, 3H); 1.53–1.74 (m, 2H); 2.12 (s, 3H);
2.49 (ddd, J¼18.4, 7.0, 5.0 Hz, 1H); 2.54–2.60 (m, 1H);
2.60–2.66 (m, 1H); 2.76 (ddd, J¼18.4, 7.8, 5.2 Hz, 1H);
3.13 (td, J¼5.3, 2.0 Hz, 1H); 3.20 (d, J¼2.0 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3): d 9.3, 24.7, 29.6, 30.6, 36.2,
59.2, 59.3, 206.3, 206.4. Anal. calcd for C9H14O3: C, 63.51;
H, 8.29. Found: C, 63.29; H, 8.15.
3.4.3. 1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octan-2-one
(7c).15 Yield: 1.07 g (69%); mp 53–54 8C (hexane) [Lit.12
mp 52.7–53.4 8C (hexane/Et2O)]. IR (CCl4): n 2933, 2867,
3.3.2. trans-1-(3-Methyl-2-oxiranyl)-1,4-hexanedione
(6b). Yield: 1.53 g (90%); colourless liquid. IR (film): n
2976, 2939, 1714, 1462, 1421, 1360, 1235, 1115, 1043,
1
1734, 1453, 1373, 1200, 1187, 1053, 960 cm21. H NMR
1
1008, 973, 844 cm21. H NMR (400 MHz, CDCl3): d 1.03
(400 MHz, CDCl3): d 1.34 (s, 1H); 1.53 (s, 1H); 2.13 (dd,
J¼8.8, 5.6 Hz, 2H); 2.36–2.57 (m, 2H); 3.55 (d, J¼8.0 Hz,
1H); 3.91 (d, J¼8.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3):
d 15.1, 23.9, 32.6, 36.6, 72.9, 84.6, 108.1, 206.4. Anal. calcd
for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.40; H, 7.61.
(t, J¼7.2 Hz, 3H); 1.39 (d, J¼5.2 Hz, 3H); 2.45 (q,
J¼7.2 Hz, 2H); 2.48–2.68 (m, 3H); 2.73–2.83 (m, 1H);
3.18 (d, J¼1.6 Hz, 1H); 3.27 (qd, J¼5.2, 1.6 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3): d 7.7, 17.5, 30.7, 35.0, 35.7,
54.4, 60.6, 206.4, 209.4. Anal. calcd for C9H14O3: C, 63.51;
H, 8.29. Found: C, 63.73; H, 8.16.
3.5. Preparation of (6)-endo-brevicomin (1b), (6)- endo-
isobrevicomin (1d) and (6)-frontalin (1e)
3.3.3. 1-(2-Methyl-2-oxiranyl)-1,4-pentanedione (6c).
Yield: 1.48 g (95%); colourless liquid. IR (CCl4): n 2973,
3.5.1. (6)-endo-Isobrevicomin (1d). To a stirred solution
of ketone 7b (0.34 g, 2 mmol) and 1,2-ethanedithiol
(0.2 mL, 2.4 mmol) in CH2Cl2 (10 mL) was slowly added
a solution of BF3·Et2O (0.43 g, 3 mmol) in CH2Cl2 (5 mL)
at 25 8C. The reaction mixture was stirred at 25–0 8C for
12–14 h, treated with aqueous 10% NaOH (10 mL) and
extracted with CH2Cl2 (3£5 mL). The combined extracts
were dried (Na2SO4) and concetrated in vacuo. Column
chromatography (SiO2, benzene) of the residue gave the
ethylene thioketal of ketone 7b. Yield: 0.30 g (61%);
1
2907, 1707, 1387, 1160, 1067, 960, 920 cm21. H NMR
(400 MHz, CDCl3): d 1.49 (s, 3H); 2.17 (s, 3H); 2.45–2.54
(m, 1H); 2.56–2.67 (m, 2H) 2.77–2.85 (m, 1H); 2.86 (d,
J¼5.2 Hz, 1H); 3.14 (d, J¼5.2 Hz, 1H). 13C NMR
(100.6 MHz, CDCl3): d 16.4, 29.1, 29.7, 36.5, 52.3, 59.5,
206.7, 208.1. Anal. calcd for C8H12O3: C, 61.52; H, 7.74.
Found: C, 61.73; H, 7.55.
3.4. 6,8-Dioxabicyclo[3.2.1]octan-2-ones (7a–c). General
procedure
1
colourless liquid. H NMR (400 MHz, CDCl3): d 0.96 (t,
J¼7.4 Hz, 3H); 1.48 (d, J¼6.4 Hz, 3H); 1.67–1.77 (m, 3H);
1.91 (ddd, J¼13.6, 11.6, 5.2 Hz 1H); 2.05 (ddt, J¼1.6, 5.6,
13.6 Hz, 1H); 2.47 (ddd, J¼14.0, 11.6, 6.0 Hz, 1H); 3.04
(ddd, J¼11.5, 9.2, 4.7 Hz, 1H); 3.17–3.31 (m, 2H), 3.44 (dt,
J¼10.9, 4.6 Hz 1H), 4.18–4.26 (m, 2H). 13C NMR
(100.6 MHz, CDCl3): d 6.9, 15.2, 30.0, 34.3, 36.4, 36.6,
40.9, 67.6, 76.1, 85.3, 108.3.
To a stirred solution of 1-(2-oxiranyl)-1,4-alkanedione
6a–c (10 mmol) in CH2Cl2 (240 mL) was added BF3·OEt2
(0.42 g, 3.3 mmol). The reaction mixture was stirred at
room temperature for 4–5 h, treated with aqueous 10%
NaOH (20 mL) and extracted with CH2Cl2 (3£10 mL). The
extracts were dried (Na2SO4) and the solvent was removed.
Compounds 7a–c were isolated by distillation under
reduced pressure or by recristallization.
A solution of ethylene thioketal of ketone 7b (246 mg,
1 mmol) in EtOH (30 mL) was refluxed for 4 h with W2
Raney nickel (5 g). After cooling the catalyst was removed
by filtration. The filtrate was concentrated under atmo-
spheric pressure and (^)-endo-isobrevicomin (1d) was
isolated by column chromatography (pentane–Et2O, 19:1).
Yield: 131 mg (84%); colourless liquid. All spectral data
were identical with those reported for 1d.3,7e
3.4.1. endo-7-Ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]-
octan-2-one (7a).14 Yield: 1.45 g (85%); colourless liquid;
bp 87–88 8C/10 Torr. IR (film): n 2970, 2940, 2880, 1729,
1448, 1384, 1225, 1200, 1172, 1084, 1040, 969, 896,
853 cm21
.
1H NMR (400 MHz, CDCl3): d 0.93 (t,
J¼7.4 Hz, 3H); 1.38 (dquint, J¼14.4, 7.2 Hz, 1H); 1.47–
1.61 (m, 1H); 1.54 (s, 3H); 2.01–2.10 (m, 2H); 2.32 (td,
J¼18.4, 8.4 Hz, 1H); 2.44 (ddd, J¼18.4, 7.6, 4.0 Hz, 1H);
3.98 (td, J¼7.2, 4.8 Hz, 1H); 4.26 (d, J¼4.8 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3): d 10.3, 22.5, 24.2, 33.3, 34.2,
3.5.2. (6)-endo-Brevicomin (1b). Ethylene thioketal of
ketone 7a14 was prepared from 7a (0.34 g, 2 mmol) in the
same manner as described above. Yield: 0.26 g (53%);

1478
V. I. Tyvorskii et al. / Tetrahedron 60 (2004) 1473–1479
1
colorless liquid. H NMR (400 MHz, CDCl3): d 1.09 (t,
J¼7.4 Hz, 3H); 1.45 (s, 3H); 1.69–2.05 (m, 5H); 2.45 (ddd,
J¼13.5, 11.6, 6.0 Hz, 1H); 3.03 (ddd, J¼11.3, 9.5, 4.8 Hz,
1H); 3.17–3.31 (m, 2H); 3.40 (dt, J¼10.9, 4.5 Hz, 1H); 4.01
(ddd, J¼8.8, 5.0, 3.9 Hz, 1H); 4.22 (dd, J¼3.9, 1.6 Hz, 1H).
13C NMR (100.6 MHz, CDCl3): d 11.9, 22.7, 24.1, 35.9,
36.4, 36.5, 40.7, 67.5, 82.1, 85.0, 106.4.
the solvent was evaporated. The crude product was purified
by recrystallization (hexane–Et2O, 10:1). Yield: 150 mg
(60%); mp 61.5–62.5 8C (hexane–Et2O). IR (CCl4): n
2973, 2933, 2880, 1373, 1347, 1187, 960, 920, 867,
733 cm21
.
1H NMR (400 MHz, CDCl3): d 1.03 (t,
J¼7.2 Hz, 3H); 1.44 (s, 3H); 1.74–1.95 (m, 4H); 2.00–
2.08 (m, 1H); 2.22 (qd, J¼10.9, 6.8 Hz, 1H); 3.02 (s, 3H);
4.08 (td, J¼7.3, 3.9 Hz, 1H); 4.34 (t, J<4.0 Hz, 1H); 4.88
(ddd, J¼10.9, 6.2, 4.4 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3): d 11.3, 21.4, 23.7, 24.6, 35.2, 38.3, 75.8, 75.9, 82.3,
106.8.
This material (246 mg, 1 mmol) was converted to (^)-endo-
brevicomin (1b) in 80% yield.14 All spectral data were
identical with those reported for 1b.2g,6d,14
3.5.3. (6)-Frontalin (1e). Ethylene thioketal of ketone 7c15
was prepared from 7c (0.31 g, 2 mmol) in the same manner
as described above. Yield: 0.44 g (95%); colorless liquid.
1H NMR (400 MHz, CDCl3): d 1.43 (s, 3H); 1.59 (s, 3H);
1.79 (dd, J¼13.2, 5.4 Hz, 1H); 1.90 (td, J¼12.8, 5.4 Hz, 1H);
2.11 (dd, J¼14.2, 5.0 Hz, 1H); 2.33–2.43 (m, 1H); 3.11–3.24
(m, 2H); 3.28–3.4 (m, 2H); 3.62 (d, J¼8.0 Hz, 1H); 4.05 (d,
J¼8.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d 20.1, 23.9,
36.8, 38.1, 39.3, 40.2, 71.8, 74.4, 86.9, 108.3.
3.6.3. (1R p,3S p,4S p,5S p)-3-Ethyl-1-methyl-2,8-dioxa-
bicyclo[3.2.1]octan-4-ol (9a).3 A solution of alcohol 8a
(172 mg, 1 mmol) and TsOH (8.6 mg, 0.05 mmol) in ether
(3 mL) was kept for 3 h at room temperature. The solvent
was evaporated and the residue was recrystallized. Yield:
138 mg (80%); mp 64–65 8C (hexane). 1H NMR (400 MHz,
CDCl3): d 0.94 (t, J¼7.4 Hz, 3H); 1.46 (s, 3H); 1.39–1.51
(m, 1H); 1.69–2.10 (m, 5H); 2.35 (br. s, 1H); 3.30 (td,
J¼8.4, 2.7 Hz, 1H); 3.47 (dd, J¼8.4, 4.2 Hz, 1H); 4.27 (dd,
1
J¼6.4, 4.2 Hz, 1H). H NMR (400 MHz, C6D6): d 0.92
This material was converted to (^)-frontalin (1e) in 72%
yield.12 All spectral data were identical with those reported
for 1e.4b,c
(br.s, 1H); 1.04 (t, J¼7.4 Hz, 3H); 1.52 (s, 3H); 1.45–1.55
(m, 2H); 1.57–1.67 (m, 1H); 1.69–1.80 (m, 2H); 1.88 (ddd,
J¼12.0, 9.3, 4.0 Hz, 1H); 3.22 (td, J¼8.3, 2.3 Hz, 1H);
3.25–3.31 (m, 1H); 4.08 (dd, J¼6.8, 3.8 Hz, 1H). 13C NMR
(100.6 MHz, CDCl3): d 9.5, 23.4, 23.6, 25.3, 33.8, 68.0,
74.9, 78.1, 105.3. 13C NMR (100.6 MHz, C6D6): d 9.9,
23.91, 23.93, 26.0, 34.3, 68.6, 75.2, 78.3, 105.3.
3.6. Preparation of hydroxy compounds 8a, 9a and their
derivatives 8b, 9b
3.6.1. (1R p,2S p,5S p,7S p)-endo-7-Ethyl-5-methyl-6,8-
dioxabicyclo[3.2.1]octan-2-ol (8a). To a stirred suspension
of LiAlH4 (0.06 g, 1.4 mmol) in Et2O (3 mL) was slowly
added a solution of ketone 7a (0.34 g, 2 mmol) in Et2O
(2 mL). The reaction mixture was stirred for 2 h, treated
with 5% HCl (about 4 mL) until pH¼7.5 and extracted with
Et2O (3£5 mL). The organic extracts were dried (Na2SO4)
and filtered through a short pad of silica gel to provide, after
concentration, alcohol 8a (purity.95%; 1H NMR spec-
troscopy). Yield: 0.33 g (96%); colourless liquid. IR (CCl4):
n 3480, 2994, 2947, 2880, 1480, 1401, 1267, 1213, 1186,
1093, 1053, 1020, 920, 893, 867 cm21. 1H NMR (400 MHz,
C6D6): d 1.12 (t, J¼7.4 Hz, 3H); 1.56 (s, 3H); 1.59–1.78
(m, 4H); 1.91–2.19 (m, 2H); 3.81–3.91 (m, 1H); 4.01 (t,
J<4.4 Hz, 1H); 4.12–4.20 (m, 1H). 13C NMR (100.6 MHz,
C6D6): d 11.9, 22.1, 24.4, 27.3, 35.4, 68.7, 78.2, 82.9, 106.6.
MS (70 eV) m/z (%): 172 (0.6), 143 (1), 115 (4), 114 (19),
113 (1), 112 (2), 102 (1), 101 (6), 99 (3), 97 (4), 96 (1), 95
(3), 87 (1), 86 (9), 85 (12), 84 (21), (83 (21), 81 (5), 79 (1),
74 (1), 73 (20), 72 (12), 71 (23), 70 (6), 69 (7), 68 (1), 67 (4),
61 (18), 60 (2), 59 (11), 58 (25), 57 (24), 56 (21), 55 (26), 54
(4), 53 (4), 45 (5), 44 (5), 43 (100), 42 (6), 41 (22), 40 (2), 39
(15). Anal. calcd for C9H16O3: C, 62.77; H, 9.36. Found: C,
62.51; H, 9.23.
3.6.4. (1S p,2S p,3S p,5R p)-3-Ethyl-5-methyl-4,8-dioxa-
bicyclo[3.2.1]oct-2-yl methanesulfonate (9b). To a stirred
solution of alcohol 9a (0.34 g, 2 mmol) and Et3N (0.56 mL,
4 mmol) in ether (7 mL) was added MsCl (0.35 g, 3 mmol)
at 0 8C. The reaction mixture was stirred at room
temperature for 2 h, treated with saturated NaHCO3
(10 mL) and extracted with ether (3£5 mL). The organic
extract was dried (Na2SO4) and solvent was evaporated. The
crude product was purified by recristallization (hexane).
Yield: 0.45 g (90%); mp 73–74 8C (hexane). 1H NMR
(400 MHz, CDCl3): d 0.95 (t, J¼7.4 Hz, 3H); 1.48 (s, 3H);
1.43–1.56 (m, 1H); 1.67–1.79 (m, 1H); 1.82–1.94 (m, 1H);
1.99–2.10 (m, 3H); 3.02 (s, 3H); 3.51 (td, J¼8.9, 2.8 Hz,
1H); 4.39 (dd, J¼8.9, 4.3 Hz, 1H); 4.60 (dd, J¼6.2, 4.3 Hz,
1H). 13C NMR (100.6 MHz, CDCl3): d 9.0, 23.1, 24.0, 24.9,
33.5, 38.3, 71.5, 74.9, 75.9, 105.8.
Methanesulfonate 9b could also be obtained from alcohol
8a (0.34 g, 2 mmol) in the same manner as from 9a. Yield:
0.45 g (90%).
Acknowledgements
3.6.2. (1R p,2S p,5S p,7S p)-endo-7-Ethyl-5-methyl-6,8-
dioxabicyclo[3.2.1]oct-2-yl methanesulfonate (8b). To a
stirred solution of NaH (50% in oil) (192 mg, 4 mmol) and
imidazole (2.5 mg) in THF (5 mL) was added alcohol 8a
(172 mg, 1 mmol). The reaction mixture was stirred at room
temperature for 1 h and MsCl (0.4 mL, 5 mmol) was added.
The resulting mixture was stirred for 7 h, treated with
saturated NaHCO3 (10 mL) and extracted with ether
(3£5 mL). The organic extract was dried (Na2SO4) and
The authors are grateful to the Ministry of Education of
Belarus and the INTAS program of the European Union.
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