A convenient route to 2,6-dialkyl-2,3-dihydro-4H-pyran-4-ones via oxidative cleavage of protected 1-(2-oxoalkyl)-cyclopropanols. Synthesis of (±)-hepialone and its natural congener

Article abstract of DOI:10.1016/j.tetlet.2011.07.042

An efficient strategy for the synthesis of 2,6-dialkyl-2,3-dihydro-4H- pyran-4-ones has been developed, the key steps of which are oxidative cleavage of the three-membered rings of 1-(2-oxoalkyl)-cyclopropanols and acid-promoted cyclization of the resulting β-hydroxyketones.

Full text of DOI:10.1016/j.tetlet.2011.07.042

Tetrahedron Letters 52 (2011) 4792–4794
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Tetrahedron Letters
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A convenient route to 2,6-dialkyl-2,3-dihydro-4H-pyran-4-ones
via oxidative cleavage of protected 1-(2-oxoalkyl)-cyclopropanols.
Synthesis of (±)-hepialone and its natural congener
⇑
Dmitry A. Astashko , Vladimir I. Tyvorskii
Department of Organic Chemistry, Belarusian State University, Nezalezhnasti Avenue, 4, 220030 Minsk, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient strategy for the synthesis of 2,6-dialkyl-2,3-dihydro-4H-pyran-4-ones has been developed,
the key steps of which are oxidative cleavage of the three-membered rings of 1-(2-oxoalkyl)-cycloprop-
anols and acid-promoted cyclization of the resulting b-hydroxyketones.
Received 5 April 2011
Revised 22 June 2011
Accepted 11 July 2011
Available online 3 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropanols
Oxidation
b-Hydroxyketones
Pheromones
Substituted cyclopropanols find wide application as versatile
intermediates in organic synthesis due to their ability to be easily
transformed into various classes of organic compounds via selec-
tive cleavage of the three-membered rings.1 These reactive sub-
stances have become readily available since the discovery of the
intriguing reaction between esters and Grignard reagents in the
presence of Ti(IV) isopropoxide, a method referred to as the
Polyfunctionalized pyran derivatives are structures that com-
monly appear in numerous natural products and biologically active
7
,8
9
compounds. Several methods, such as the hetero-Diels–Alder
9a
reaction, transition metal catalyzed cyclization of b-hydroxy
9
b,c
9d–f
enones
or ynones
and acid-catalyzed cyclization of 5-hydro-
have been developed for the synthesis of 2,3-
9
g–k
xy-1,3-diketones
dihydro-4H-pyran-4-one derivatives. Despite their utility, these
methods have some limitations related to preparative scope. More-
over, in some cases, the preparation of suitable precursors for these
reactions or synthetic procedures is difficult and/or expensive. In
this Letter, we report a new strategy for the synthesis of 2,6-dial-
kyl-2,3-dihydro-4H-pyran-4-ones, which includes, as key steps,
the Kulinkovich cyclopropanation of a protected 3-ketocarboxylic
acid ester followed by oxidative cleavage of the resulting cyclopro-
panol to form a b-hydroxyketone and, finally, acid-promoted cycli-
zation of the latter compound (as summarized in Scheme 2).
The procedure for the Kulinkovich cyclopropanation of pro-
tected ethyl acetoacetate (1a, Scheme 3) with ethylmagnesium
2
a
Kulinkovich reaction.
3
Recently, we reported an effective method for the oxidation of
substituted cyclopropanols using molecular oxygen in the pres-
ence of Mn(II) abietate (Scheme 1).
b-Hydroperoxyketones formed in this reaction as a result of
C1–C2 bond cleavage of the cyclopropane ring could be transformed
3
,4a
easily into
a,b-epoxyketones under the action of aqueous KOH.
5
Alternatively, they could be reduced to 1,3-diols or b-hydroxyke-
tones (Scheme 1). Blanco et al. proposed triphenylphosphine as
a reducing agent to perform the latter transformation. Herein, we
4
b
4
show that less expensive zinc in acetic acid produced comparable
yields of aldols in this reaction. Earlier,5 we demonstrated the syn-
thetic potential of the methods described (Scheme 1) with the use of
,6
10
bromide is described in the literature, and can be carried out
2
b
using a catalytic version of this reaction. Unfortunately, the reac-
tion of 1a with propyl- or butylmagnesium bromide under the
same conditions as above led to a complex mixture of products.
This transformation proceeded more cleanly when a large excess
functionalized a,b-epoxyketones and 1,3-diols as key intermediates
for the efficient synthesis of 6,8-dioxabicyclo[3.2.1]octane and 2,9-
dioxabicyclo[3.3.1]nonane derivatives, some of which are insect
pheromones.
2
(5 equiv) of Grignard reagent in THF/Et O (1:2) was added slowly
1
1
to a refluxing solution of compound 1a,b in THF in the presence
of 1 equiv of titanium(IV) isopropoxide (Scheme 3, Table 11 ).
Reaction of 1a with hex-1-ene and cyclopentylmagnesium bro-
mide in the presence of chlorotitanium triisopropoxide under the
2a
⇑
Corresponding author. Tel.: +375 17 2095459; fax: +375 17 2265609.
E-mail addresses: astashko@bsu.by, diels75@gmail.com (D.A. Astashko).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.042

D. A. Astashko, V. I. Tyvorskii / Tetrahedron Letters 52 (2011) 4792–4794
4793
O
O
OOH
R2
O
OH
R2
HO
R1
Mn(II) abietate, O
2
/PhH
R1
R1
R2
KOH/H O
reduction
2
O
O
O
OH
R2
OH OH
R1 R2
or
R1
R2
R1
Scheme 1.
Table 1
Synthesis of b-hydroxyketones
2
OH
O
R CH CH MgBr
O
R1
O
O
O
2
2
R2
R1
Kulinkovich
cyclopropanation
O
R1
R2
2 (% yield) (3, % yield)a
4 (% yield)b
Entry
c
1
2
3
4
5
CH
CH
CH
3
3
3
H
CH
C H
2 5
CH
n-C
2a (80)
4a (52)
4b (53)
4c (60)
4d (51)
4e (58)
2b (63) (3b, 16)d
2c (62) (3c, 13)
2d (60) (3d, 14)d
2e (76) (3e, 16)
3
O
C
2
H
5
3
acid-promoted
cyclisation
O
OH
R2
CH
3
4 9
H
1
2
) oxidation
) reduction
O
R1
O
a
Yield determined from 1H NMR spectroscopic data.
The yields are given over two steps, Ph P/Et O and Zn/AcOH gave comparable
3 2
R1
R2
O
b
yields in all cases.
Scheme 2.
c
was used.10
4
A catalytic amount (0.2 equiv) of Ti(Oi-Pr)
d
The corresponding secondary alcohol was isolated and characterized by 1H and
13
C NMR spectroscopy during the second step.
above mentioned conditions proved to be the optimal method for
the synthesis of compound 2e. Cis-1,2-disubstituted cyclopropa-
nols 2b–e were isolated in good yields (with cis:trans dialkyl
1
3
diastereoselectivity of >9:1 ), and all the samples contained 15–
O
O
1
4
2
0% of a known, inseparable minor product corresponding to
O
OH
the secondary alcohol 3b–e, which did not suppress further trans-
formation of compounds 2 into b-hydroxyketones 4, and could be
removed in the final (oxidation) step of the reaction sequence. Oxi-
dation of cyclopropanols 2a–e with oxygen in the presence of 1–
O
O
H2SO4 (50%)
CH Cl r.t.
R1
R2
R1
R2
2
2,
4a-e
1
2
5a: R =CH , R =H
(74%)
(82%)
(86%)
(90%)
3
1
2
1
.5 mol % of manganese(II) abietate followed by reduction with
5b: R =CH , R =CH
3 3
1
2
Zn/AcOH or Ph P/Et O led to the desired aldols 4a–e in overall
3
2
5c: R =CH , R =C H
3 2
5
3
1
2b
1
2
yields of 51–60% (Scheme 3, Table 1 ).
5d: R =C H , R =CH
2 5
1
2
The structures of the b-hydroxyketones were confirmed by
NMR and IR spectroscopy, as well as by microanalysis. It is note-
worthy, that compound (R)-4c was previously synthesized by
Curran and Heffner from 2-methyl-2-(2-nitroethyl)-l,3-dioxole
via the corresponding isoxazoline derivative in 10% yield over 6
steps.
In our experiments, reactions of b-hydroxyketones 4a–e with
cold 50% sulfuric acid in methylene chloride gave the target 2,6-
dialkyl-2,3-dihydro-4H-pyran-4-ones 5a–e in good to excellent
yields (Scheme 4). Compound 5c is (±)-hepialone, a natural pher-
omonal component of the male swift moth, Hepialus californicus
3 9
4
5e: R =CH , R =n-C H (93%)
Scheme 4.
1
5
Bdv.17 (the overall yield starting from 1a was 51%), and pyranone
5d is the main component of the pheromone blend of the male
swift moth Hepialus hecta L. (the overall yield starting from 1b
was 46%). It should be noted that an attempt to use diluted hydro-
chloric acid in diethyl ether
unsuccessful.
1
8
1
6
15
for the cyclization of 4c was
O
2
OH
OH
O
R1
O
R (CH2)2MgBr, Ti(Oi-Pr)4
O
R1
O
O
R1
O
R2
R2
O
Et O/THF (2:1), reflux
2
1
1
1
a: R =Me
2a-e
3a-e
1
b: R =Et
R2
,
c-C H MgCl, ClTi(Oi-Pr)
5 9 3
Et O/THF (2:1), reflux
2
for 2e
O
OH
R2
1
. Mn(II) abietate/O2,PhH
. Zn/AcOH or Ph P/Et O
O
R1
O
2a-e
2
3
2
4
a-e
Scheme 3.

4
794
D. A. Astashko, V. I. Tyvorskii / Tetrahedron Letters 52 (2011) 4792–4794
In summary, we have described a new and convenient route to
,6-disubstituted 2,3-dihydro-4H-pyran-4-ones via Kulinkovich
filtered and extracted with Et
with brine (15 ml), dried over Na
pressure. Purification of the residue by column chromatography on silica gel
petroleum ether/EtOAc, gradient) gave 1.38 g of an 81:19 mixture of
cyclopropanol 2d (60% yield) and the corresponding secondary alcohol 3d
14% yield) as a colorless liquid.
Spectroscopic data for cyclopropanol 2d: 1H NMR (400 MHz, CDCl
H); 0.82–0.94 (m, 2H); 0.91 (t, J = 7.3 Hz, 3H); 0.97 (s, 3H); 1.67 (d, J = 14.9 Hz,
2
O (3 Â 15 ml). The organic extracts were washed
2
SO and concentrated under reduced
4
2
cyclopropanation of readily available protected 3-oxocarboxylic
acid esters followed by cleavage of the resulting cyclopropanols
to form the corresponding b-hydroxyketones and their subsequent
acid-promoted cyclization. We have also successfully applied this
methodology for the preparation of (±)-hepialone and its isomer
±)-6-ethyl-2-methyl-2,3-dihydro-4H-pyran-4-one, which are the
natural pheromonal components of the male swift moths, Hepialus
hecta L. and Hepialus californicus Bdv.
(
(
3
): d = 0.14 (m,
1
1H); 1.70–1.81 (m, 2H); 2.15 (d, J = 14.9 Hz, 1H); 3.94–4.06 (m, 4H); 4.08 (s,
1
6
H). 13C NMR (100.6 MHz, CDCl
4.87, 64.90, 113.2.
3
): d = 7.8, 14.4, 17.3, 20.1, 30.6, 38.0, 56.3,
(
Cyclopropanol 2c was prepared according to the above typical procedure from
ethyl acetoacetate (1a) and butylmagnesium bromide in 62% yield (Table 1,
entry 3).
Spectroscopic data for cyclopropanol 2c: 1H NMR (400 MHz, CDCl
): d = 0.19 (dd,
J = 5.4 Hz, 4.4 Hz, 1H); 0.80–0.91 (m, 2H); 0.94 (t, J = 7.3 Hz, 3H); 1.06 (m, 1H);
.34 (m, 1H); 1.42 (s, 3H); 1.63 (d, J = 14.8 Hz, 1H); 2.24 (d, J = 14.8 Hz, 1H);
3
References and notes
1
13
1
.
.
For reviews, see: (a) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2547–2632; (b)
Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15–61.
(a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org.
Khim. 1989, 25, 2244–2245; Russ. J. Org. Chem. 1989, 25, 2027–2028.; (b)
Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A. Synthesis 1991, 234.
Kulinkovich, O. G.; Astashko, D. A.; Tyvorskii, V. I.; Ilyina, N. A. Synthesis 2001,
3.94 (br s, 1H), 3.95–4.02 (m, 4H). C NMR (100.6 MHz, CDCl
3
): d = 13.7, 19.0,
23.1, 24.7, 25.0, 40.6, 56.5, 64.4, 64.6, 111.3.
2
(b) Typical procedure for the oxidative cleavage of 1-(2-alkyl-[1,3]dioxolan-2-
ylmethyl)-2-alkyl-cyclopropanols 2. Synthesis of 1-(2-ethyl-[1,3]dioxolan-2-yl)-4-
hydroxy-pentan-2-one (4d, Table 1, entry 4): Air was bubbled for 2–3 h through
a solution of 2d (1.38 g, 6 mmol, 81:19 mixture with 3d) and Mn(II) abietate
(0.1 g, 1 mol %) in dry benzene (60 ml) with vigorous stirring at rt. The solvent
was evaporated under reduced pressure and the residue dissolved in AcOH
(10 ml). Zn powder (0.33 g, 5 mmol) was added to this solution in portions and
3.
4.
5.
6.
7.
8.
1
453–1455.
(a) Barnier, J.-P.; Morisson, V.; Blanco, L. Synth. Commun. 2001, 31, 349–357; (b)
Morisson, V.; Barnier, J.-P.; Blanco, L. Tetrahedron Lett. 1999, 40, 4045–4046.
Tyvorskii, V. I.; Astashko, D. A.; Kulinkovich, O. G. Tetrahedron 2004, 60, 1473–
the mixture stirred for 2 h at rt. Next, saturated NaHCO
added and the solution was extracted with Et
O (3 Â 15 ml). The organic
extracts were washed with aqueous NaHCO SO ) and
(3 Â 10 ml), dried (Na
3
(40 ml) was carefully
1
479.
Astashko, D. A.; Kulinkovich, O. G.; Tyvorskii, V. I. Zh. Org. Khim. 2006, 42, 736–
40; Russ. J. Org. Chem. 2006, 42, 719–723.
2
3
2
4
7
concentrated under reduced pressure. Column chromatography of the residue
on silica gel (petroleum ether/EtOAc, gradient) gave 1.03 g of b-hydroxyketone
4d (51% overall yield from ester 1b) and 0.26 g of unreacted secondary alcohol
3d, both as colorless liquids.
For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309–3362; (b) Faul,
M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407–2474.
For examples, see: (a) Yoo, N. H.; Jang, D. S.; Yoo, J. L.; Lee, Y. M.; Kim, Y. S.; Cho,
J. H.; Kim, J. S. J. Nat. Prod. 2008, 71, 713–715; (b) Bradley, D. T.; Susan, H.;
Domagala, J.; Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Prasad, J. V. N. V.;
Ferguson, D.; Graham, N.; Hupe, D.; Nouhan, C.; Tummino, P. J.; Humblet, C.;
Lunney, E. A.; Pavlovsky, A.; Rubin, J.; Gracheck, S. J.; Baldwin, E. T.; Bhat, T. N.;
Erickson, J. V.; Gulnik, S. V.; Liu, B. J. Med. Chem. 1997, 40, 3781–3792; (c) Sun,
C.-L.; Pang, R.-F.; Zhang, H.; Yang, M. Bioorg. Med. Chem. Lett. 2005, 15, 3257–
Spectroscopic and microanalysis data for b-hydroxyketone 4d: IR (CCl
4
): 3561,
À1
1
2978, 2884, 1704, 1373, 1069, 948 cm
. H NMR (400 MHz, CDCl ): d = 0.86 (t,
3
J = 7.4 Hz, 3H); 1.12 (d, J = 6.4 Hz, 3H); 1.66 (q, J = 7.4 Hz, 2H); 2.56 (dd, J = 17.9,
9.5 Hz, 1H); 2.66 (dd, J = 17.9, 3.1 Hz, 1H); 2.69 (s, 2H); 3.20 (br s, 1H); 3.92 (s,
4H); 4.15 (dqd, J = 9.5, 6.4, 3.1, 1H). 13C NMR (100.6 MHz, CDCl
30.7, 50.0, 52.2, 63.6, 64.9, 109.9, 209.2. Anal. Calcd for C10
8.97. Found: C, 59.31; H, 8.83.
): d = 7.7, 22.2,
18 4
H O : C, 59.39; H,
3
3
5
262; (d) Lukesh, J. M.; Donaldson, W. A. Tetrahedron Lett. 2005, 46, 5529–
531; (e) Perkins, M. V.; Sampson, R. A. Org. Lett. 2001, 3, 123–126; (f)
b-Hydroxyketone 4c was prepared according to the above typical procedure in
60% overall yield from 1a (Table 1, entry 3). All spectral data were identical
with those reported in the literature.15
Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125,
793–3798.
3
9
.
For representative examples, see: (a) Danishefsky, S.; Kerwin, J. F., Jr.;
Kobayashi, S. J. Am. Chem. Soc. 1982, 104, 358–360; (b) Reiter, M.; Ropp, S.;
Gouverneur, V. Org. Lett. 2004, 6, 91–94; (c) Reiter, M.; Turner, H.; Mills-Webb,
R.; Gouverneur, V. J. Org. Chem. 2005, 70, 8478–8485; (d) Wang, C.; Forsyth, C. J.
Org. Lett. 2006, 8, 2997–3000; (e) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.;
Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47, 7927–7930; (f) Fuwa, H.;
Matsukida, S.; Sasaki, M. Synlett 2010, 1239–1242; (g) Gao, B.; Yu, Z.; Fu, Z.;
Feng, X. Tetrahedron Lett. 2006, 47, 1537–1539; (h) Yu, C.; Zheng, F.; Ye, H.;
Zhong, W. Tetrahedron 2009, 65, 10016–10021; (i) Ahmad, R.; Ahmad Khera, R.;
Villinger, A.; Langer, P. Tetrahedron Lett. 2009, 50, 3020–3022; (j) Ahmad Khera,
R.; Ahmad, R.; Ullah, I.; Abid, O. U. R.; Fatunsin, O.; Sher, M.; Villinger, A.;
Langer, P. Helv. Chim. Acta 2010, 93, 1705–1715; (k) MacDonald, F. K.; Burnell,
D. J. J. Org. Chem. 2009, 74, 6973–6979.
13. (a) Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 9345–9346; (b)
Kananovich, D. G.; Kulinkovich, O. G. Tetrahedron 2008, 64, 1536–1547.
14. Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem. 2007, 2121–2132.
15. Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585–4595.
16. Typical procedure for the acid-promoted cyclization of b-hydroxyketones 4a–e.
Synthesis of 2-ethyl-6-methyl-2,3-dihydro-4H-pyran-4-one ((±)-hepialone, 5c)
and its natural congener, 6-ethyl-2-methyl-2,3-dihydro-4H-pyran-4-one (5d):
Cold H
4d (5 mmol, 1.01 g) in CH
stirred for 2 h at rt, carefully quenched with saturated NaHCO
extracted with CH Cl
(3 Â 5 ml). The organic extracts were washed with
saturated NaHCO SO and concentrated under
(3 Â 5 ml), dried over Na
2
SO
4
(50% aq, 1.5 ml) was added to a solution of b-hydroxyketone 4c or
Cl (10 ml) with vigorous stirring. The mixture was
(10 ml) and
2
2
3
2
2
3
2
4
reduced pressure. Purification of the residue by column chromatography on
silica gel (petroleum ether/EtOAc, gradient) gave the corresponding pyranones
5c,d (86% and 90% yields, respectively) as colorless liquids. All spectral data
were identical with those reported in the literature.1
1
0. Raiman, M. V.; Il’ina, N. A.; Kulinkovich, O. G. Synlett 1999, 1053–1054.
1. For the synthesis of 3-oxopentanoic acid ethyl ester (unprotected 1b), see:
Wierenga, W.; Skulnick, H. I. Org. Synth. Coll. 1990, 7, 213.
1
5,17,18c
1
2. (a) Typical procedure for the Kulinkovich cyclopropanation of (2-alkyl-
17. Kubo, I.; Matsumoto, T.; Wagner, D. L.; Shoolery, J. N. Tetrahedron Lett. 1985, 26,
563–566.
[
1,3]dioxolan-2-yl)-acetic acid ethyl esters 1. Synthesis of 1-(2-ethyl-
1,3]dioxolan-2-ylmethyl)-2-methyl-cyclopropanol (2d, Table 1, entry 4):
mixture of THF
O (20 ml) was slowly added to a stirred solution of ester 1d
10 mmol, 1.88 g) and Ti(Oi-Pr) (10 mmol, 3 ml) in THF (30 ml) at reflux. The
O (15 ml),
[
A
18. (a) Francke, W.; Mackenroth, W.; Schröder, W.; Schulz, S.; Tengö, J.; Engels, E.;
Engels, W.; Kittmann, R.; Schneider, D. Z. Naturforsch. 1985, 40c, 145–147; (b)
Sinnwell, V.; Schulz, S.; Francke, W.; Kittmann, R.; Schneider, D. Tetrahedron
Lett. 1985, 26, 1707–1710; (c) Mori, K.; Kisida, H. Tetrahedron 1986, 42, 5281–
5290.
solution of propylmagnesium bromide (45 mmol) in
a
(
(
10 ml) and Et
2
4
mixture was refluxed for an additional 1 h, and then treated with H
2