Improved synthesis of (R)-7-hydroxycarvone from (S)-α-pinene

Article abstract of DOI:10.1016/j.tetlet.2013.10.066

A three-step synthesis of (R)-7-hydroxycarvone (1), which is anticipated to be a valuable building block for the versatile preparation of natural products, is described. Optimization of the reaction conditions for photooxygenation and migration of (S)-α-p

Full text of DOI:10.1016/j.tetlet.2013.10.066

Tetrahedron Letters 54 (2013) 7029–7030
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved synthesis of (R)-7-hydroxycarvone from (S)-
a-pinene
⇑
Yuki Egoshi, Ryosuke Kondo, Yukiko Yoshimoto, Toru Sugiyama, Toyonobu Usuki
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-step synthesis of (R)-7-hydroxycarvone (1), which is anticipated to be a valuable building block
Received 31 July 2013
Revised 8 October 2013
Accepted 15 October 2013
Available online 23 October 2013
for the versatile preparation of natural products, is described. Optimization of the reaction conditions for
photooxygenation and migration of (S)-a-pinene 2, tetrapropylammonium perruthenate (TPAP) oxida-
tion of the generated alcohol, and a subsequent ring-opening reaction in the presence of Cu(OTf)2 led
to the synthesis of 1 with good reproducibility. The desired product 1 was thus obtained in 46% yield over
three steps.
Keywords:
7-Hydroxycarvone
Ó 2013 Elsevier Ltd. All rights reserved.
a-Pinene
Photooxygenation
Ring-opening reaction
(R)-7-Hydroxycarvone (1, Scheme 1) is anticipated to be a use-
ful building block for the versatile natural product synthesis of
compounds such as ouabain.1,2 The synthesis of 1 was previously
achieved in 10 steps from (R)-carvone in 11% overall yield.2,3
Although the most direct route to the desired product would be
via the allylic oxidation of (R)-carvone, this reaction affords unde-
sired products due to the presence of the more electron-rich iso-
propenyl group.4 McIntosh and co-workers reported the
synthesis of 1 in three steps in 45% overall yield starting from
to generate the allylic hydroperoxide 5, which was confirmed via
gas chromatography–mass spectrometry (GC–MS) analysis. With-
out purification, stereoselective migration of 5 via Ti(OiPr)4-cata-
lyzed intermolecular oxygen transfer was then achieved to give
the desired epoxy alcohol 3 in 92% yield (entry 1).5 In order to im-
prove the yield, the reaction was carried out in CH2Cl2 in the pres-
ence of Rose Bengal (RB) as an alternative photosensitizer.
(S)-a-pinene 2 via photooxygenation–migration, oxidation, and
ring-opening reactions (Scheme 1). The synthesis commenced with
photooxygenation and migration of 2 to produce epoxy alcohol 3,
which was then converted to epoxy ketone 4 via Swern oxidation.
Thus, (R)-7-hydroxycarvone
1 was synthesized via the ring-
opening of the pinene skeleton and the epoxide group in 4 using
BF3ÁEt2O. In our hands, however, 1 was initially obtained in just
1% yield under the reported conditions. Herein, we describe the
development of a reproducible version of the three step synthesis
of 1, that is, improved reaction conditions for the photooxygen-
ation of 2, Ti(OiPr)4-mediated migration, tetrapropylammonium
perruthenate (TPAP) oxidation of 3, and ring-opening of 4 using
Cu(OTf)2 as a Lewis acid.
The one-pot photooxygenation and migration of (S)-a-pinene 2
to produce epoxy alcohol 3 via the allylic hydroperoxide 5 were
investigated (Table 1). Following McIntosh’s protocol, photooxy-
genation of 3 via a stereoselective ene reaction with singlet oxygen
induced by 0.2 mol % of the photosensitizer tetraphenylporphyrine
(TPP) using a halogen lamp in CH2Cl2 at 0 °C for 3 h was carried out
⇑
Corresponding author. Tel.: +81 3 3238 3446; fax: +81 3 3238 3361.
E-mail address: t-usuki@sophia.ac.jp (T. Usuki).
Scheme 1. Three-step synthesis of (R)-7-hydroxycarvone 1 from (S)-a-pinene 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.066

7030
Y. Egoshi et al. / Tetrahedron Letters 54 (2013) 7029–7030
Table 1
Table 3
Synthesis of epoxy alcohol 3 from 2 via 5
Optimization of the ring-opening reaction of 4 to 1
Entry
Photosensitizer
(0.2 mol %)
Solvent
Time (h)
Yield (3, %)
Entry
Lewis acid
Equiv
Temperature (°C)
Time (h)
Yield (%)
Ref. 1
1
2
3
4
5
6
7
8
BF3ÁOEt2
BF3ÁOEt2
TiCl4
3
3
0
4
4
6
6
24
24
0.75
19
6
2
19
6
55
8
4
17
Ref. 1
TPP
TPP
RB
RB
RB
CH2Cl2
CH2Cl2
CH2Cl2
Acetone
Ethanol
4
3
2
2
2
95
92
rt
rt
rt
rt
rt
rt
rt
rt
40
rt
rt
rt
1
2
3
4
1.05
1.05
1.5
1.5
1.5
1.5
1.05
1.05
1.5
0.2
3
Trace
Complex mixture
Complex mixture
AlCl3
Pr(OTf)3
Nd(OTf)3
Sc(OTf)3
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
NR (43a)
NR (58a)
45
20
53
43
55
26
51
9
Table 2
10
11
12
Oxidation of epoxy alcohol 3 to afford epoxy ketone 4
2
a
Yield of recovered starting material.
Cu(OTf)2, however, gave 1 in 53% yield (entry 8). When the reaction
temperature was increased to 40 °C, the yield decreased slightly to
43% (entry 9). An investigation of the effect of the number of molar
equivalents of Cu(OTf)2 used in the reaction on the yield of 1 indi-
cated that the complex works as a non-catalytic reagent (entries
10–12). Consequently, a reproducible procedure using 1.5 equiv
of Cu(OTf)2 in CH2Cl2 at room temperature for 19 h was found to
give the desired (R)-7-hydroxycarvone 1 in 55% yield (entry 10)
as the best condition. Large scale synthesis of 1 under the same
condition gave similar yield with 30–40% recovery of starting
material.8 The relatively mild Lewis acid Cu(OTf)2 may work as a
proper non-catalytic Lewis acid via chelation to the corresponding
oxygen atoms.
Entry
Conditions
Yield (%)
Ref. 1
(COCl)2, DMSO, Et3N, CH2Cl2, À78 °C to rt
(COCl)2, DMSO, Et3N, CH2Cl2, À78 °C to rt, 2 h
Dess–Martin periodinane, CH2Cl2, 45 min
TPAP (5 mol %), NMO, MS4Å, CH2Cl2, 0 °C, 1 h
90
27
85
90
1
2
3
However, only a trace amount of epoxy alcohol 3 was obtained (en-
try 2). In highly polar solvents, such as acetone and ethanol, com-
plex mixtures were observed that included both unreacted starting
material 2 and intermediate 5, as identified by GC–MS (entries 3
and 4). Thus, the reaction using TPP was determined to provide
the most effective conditions.
In conclusion, reproducible reaction conditions for the prepara-
tion of (R)-7-hydroxycarvone 1 from (S)-a-pinene 2 via photooxy-
genation and migration, TPAP oxidation, and Cu(OTf)2-mediated
ring-opening were described. The desired product 1 was thus ob-
tained in 46% yield over three steps.
Oxidation of the obtained epoxy alcohol 3 to generate epoxy ke-
tone 4 was then investigated (Table 2). While McIntosh and co-
workers reported that the Swern oxidation of 3 proceeds in 90%
yield,1 our attempt gave the product 4 in only 27% yield (entry 1).
Dess–Martin periodinane6 and TPAP7 oxidations were attempted
to afford ketone 4 in 85% and 90% yields, respectively (entries 2
and 3). Thus, it was concluded that oxidation using TPAP with N-
methylmorpholine N-oxide (NMO), which is a well-accepted proto-
col for large scale-synthesis, was the best method for this step.
The final step in the synthesis of (R)-7-hydroxycarvone 1 in-
volved ring-opening of the pinene skeleton and the epoxide group
in 4. Previously, it was shown that the use of BF3ÁOEt2 as a Lewis
acid afforded 1 in moderate yield (55%) on a multi-gram scale,
while basic, acidic, and silylative conditions were found to cause
decomposition or no reaction.1 In our hands, however, the reaction
with BF3ÁOEt2 gave the desired product 1 in only 8% yield (Table 3,
entry 1) with poor reproducibility and decomposition of starting
material, particularly on a gram-scale. The ring-opening reaction
under various Lewis acid conditions was thus investigated. When
either TiCl4 or AlCl3 was used as the Lewis acid for 6 h, the product
was obtained in 4% and 17% yields, respectively (entries 2 and 3). In
addition, the use of typical Lewis acids, such as CuCl2, Ti(OiPr)4,
Yb(OTf)3, and Mg(OTf)2 led to no reaction (data not shown). Fur-
thermore, when lanthanide triflates, such as Pr(OTf)3 and Nd(OTf)3,
were applied to this reaction, only recovery of the starting material
was observed in 43% and 58% yields, respectively (entries 4 and 5).
Use of Sc(OTf)3 for 45 min and 19 h gave the desired product 1 in
45% and 20% yields, respectively (entries 6 and 7), along with gen-
eration of byproducts that were difficult to separate. The use of
Acknowledgment
We thank Professor Masahiro Rikukawa (Sophia University) for
his support of equipments. This work was supported in part by a
Grant-in-Aid for Young Scientists (B) from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology (MEXT), Japan.
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.066.
References and notes
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Lett. 2004, 45, 5039.
4. Büchi, G.; Wüest, H. J. Org. Chem. 1969, 34, 857.
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Soc. 1989, 111, 203.
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8. When the reaction is run on a large scale (i.e., 500 mg or more), it should be run
for less than 2 h due to the generation of byproducts that are difficult to
separate.