A convenient 3-step synthesis of (R)-7-hydroxycarvone from (S)-α-pinene

Article abstract of DOI:10.1021/jo050217h

A convenient 3-step synthesis of (R)-7-hydroxycarvone (2) has been developed starting from (S)-α-pinene (7), using photooxygenation, oxidation, and fragmentation reactions. An improved synthesis of epoxy alcohol 6 and an unusual Ti(OiPr)₄ catalyzed hydroxy epoxide to keto alcohol rearrangement are also described.

Full text of DOI:10.1021/jo050217h

A Convenient 3-Step Synthesis of
(R)-7-Hydroxycarvone from (S)-r-Pinene
Rajamma Lakshmi, T. David Bateman, and
Matthias C. McIntosh*
FIGURE 1.
Department of Chemistry and Biochemistry, University of
Arkansas, Fayetteville, Arkansas 72701
tation of strained epoxide 5 could lead to (R)-7-hydroxy-
carvone (2) (Scheme 1). Fragmentation of pinene deriv-
atives has been previously employed in several synthe-
ses.5 Epoxy ketone 5 could presumably be prepared from
oxidation of epoxy alcohol 6. A convenient synthesis of
epoxy alcohol 6 from (S)-R-pinene (7) has been reported
by Adam in a one-pot photooxygenation reaction.6
In our hands, however, treatment of R-pinene (7) with
the Adam conditions (O2, Ti(OiPr)4 (10 mol %), tetra-
phenylporphine (TPP), hν, CH2Cl2, 20 h) gave as the
major product not epoxy alcohol 6 but â-hydroxy ketone
8 (Scheme 2).7
mcintosh@uark.edu
Received February 3, 2005
To gain further insight into this unexpected result, an
authentic sample of epoxy alcohol 6 was prepared in 3
steps by known methods (Scheme 3).8 Exposure of epoxy
alcohol 6 to Ti(OiPr)4 at room temperature also afforded
rearranged alcohol 8 in 80% yield.
A convenient 3-step synthesis of (R)-7-hydroxycarvone (2)
has been developed starting from (S)-R-pinene (7), using
photooxygenation, oxidation, and fragmentation reactions.
An improved synthesis of epoxy alcohol 6 and an unusual
Ti(OiPr)4 catalyzed hydroxy epoxide to keto alcohol rear-
rangement are also described.
This result suggests that the initially formed epoxy
alcohol
6
undergoes
a
rearrangement involving
1,2-hydride shift to form â-hydroxy ketone 8 (Scheme 4).
Adam reported the formation of an enone side product
that might have been formed via â-elimination of keto
alcohol 8. The authors alluded to a rearrangement of
epoxy alcohol 6 to the enone, but provided no details.6b
Adam reported one case of formation of a hydroxy ketone
via Ti(OiPr)4-catalyzed 1,2-aryl shift in ca. 5% yield.6
Although a few examples of acid-catalyzed 1,2-hydride
shifts of epoxy alcohols have been documented,9 it is
For a projected natural product synthesis in our
laboratory we required (R)-7-hydroxycarvone (2) as a
starting material (Figure 1). Surprisingly, a literature
survey revealed that there were no reports of a practical
synthesis of (R)-7-hydroxycarvone or any derivatives that
might readily be converted to the desired alcohol. Acetate
3 has been prepared in 8% yield from racemic perillyl
acetate via CrO3 oxidation.1a Methyl ester 4 has been
synthesized in 8 steps from (R)-carvone.1b Naturally
occurring terpenoids are widely employed as chiral pool
starting materials.2 If readily accessible in large quanti-
ties, (R)-7-hydroxycarvone (2) could serve as a versatile
starting material for natural product synthesis.
The most direct route to (R)-7-hydroxycarvone would
be the allylic oxidation of (R)-carvone (1) itself. However,
oxidation of carvone affords products resulting from
oxidation of the more electron rich isopropenyl group.3
Even if the isopropenyl group were somehow masked,
regioselective allylic oxidation of the C2 alkyl substituent
of 2-alkylcyclohexenones is not well precedented.4
We therefore sought to develop a synthesis of (R)-7-
hydroxycarvone (2) starting from readily available and
inexpensive (S)-R-pinene (7) to circumvent the problem-
atic allylic oxidation step. We anticipated that fragmen-
(5) (a) Valkanans, G.; Ikonomu, N. Helv. Chim. Acta 1963, 46, 1089-
1096. (b) Kaminska, J.; Schwegler, M. A.; Hoefnagel, A. J.; van
Bekkum, H. Recl. Trav. Chim. Pays-Bas 1992, 111, 432-437.
(c) Bluthe, N.; Ecoto. J.; Fetizon, M.; Lazare, S. J. Chem. Soc., Perkin
Trans. 1 1980, 1747-51. (d) Nomura, M.; Fujihara, Y. Nippon Kagaku
Kaishi 1985, 5, 992. (e) Monteil, V.; Segura, M. L.; Aldaz, A.; Barba,
F. J. Chem. Res., Synop. 1987, 27. (f) Pellegata, R.; Dosi, I.; Ventura,
P.; Villa, M.; Lesma, G.; Palmisano, G. Helv. Chim. Acta 1987, 70, 71-
78. (g) Liu, H.-J.; Nyangulu, J. M. Tetrahedron Lett. 1989, 30, 5097-
5098. (h) Trost, B. M.; King, A. S. J. Am. Chem. Soc. 1990, 112, 408-
422. (i) Wender, P. A.; Mucciaro, T. P. J. Am. Chem. Soc. 1992, 114,
5878-9. Wender, P. A.; Floreancig, P. E.; Glass, T. E.; Natchus, M.
G.; Shuker, A. J.; Sutton, J. C. Tetrahedron Lett. 1995, 36, 4939-4942.
Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass,
T. E.; Granicher, C.; Houze, J. B.; Janichen, J.; Lee, D.; Marquess, D.
G.; McGrane, P. L.; Meng, W.; Mucciaro, T. P.; Muhlebach, M.;
Natchus, M. G.; Paulsen, H.; Rawlins, D. B.; Satkofsky, J.; Shuker, A.
J.; Sutton, J. C.; Taylor, R. E.; Tomooka, K. J. Am. Chem. Soc. 1997,
119, 2755-2756.
(6) (a) Adam, W.; Griesbeck, A.; Staab, E. Tetrahedron Lett. 1986,
27, 2839-2842. (b) Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.;
Staab, E.; Will, B. J. Am. Chem. Soc., 1989, 111, 203-212.
(7) The enantiomer of ketone 8 has been previously prepared from
(+)-trans-myrtanol via biotransformation in 5% yield: Miyazawa, M.;
Suzuki, Y.; Komeoka, H. Phytochemistry 1997, 45, 935-943.
(8) (a) Crandall, J. K.; Crawley, L. C. Org. Synth. 53, 17-21.
(b) Coxon, J. M.; Dansted, E.; Hartshorn, M. P.; Richards, K. E.
Tetrahedron 1968, 24, 1193-1197. (c) Coxon, J. M.; Dansted, E.;
Hartshorn, M. P.; Richards, K. E. Tetrahedron Lett. 1969, 10, 1149-
1150.
(1) (a) Lander, N.; Ben-Zvi, Z.; Mechoulam, R.; Martin, B.; Nordqvist,
M.; Agurell, S. J. Chem. Soc., Perkin Trans. 1 1976, 8-16. (b) Lavallee,
J.-F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslongchamps, P. Can. J.
Chem. 1992, 70, 1406.
(2) Ho, T.-L. Enantioselective Synthesis: Natural Products from
Chiral Terpenes; Wiley: New York, 1992.
(3) (a) Bu¨chi, G.; Wuest, H. J. Org. Chem. 1969, 34, 857-860.
(b) Weinges, K.; Schwarz, G. Liebigs Ann. Chem. 1993, 811-814.
(c) Lee, E.; Yoon, C. H.; Lee, Y. J. J. Bull. Korean Chem. Soc. 1997,
18, 1247-48.
(4) Naf, R.; Velluz, A.; Decorzant, R.; Naf, F. Tetrahedron Lett. 1991,
32, 753-756.
(9) (a) Morrison, G. A.; Wilkinson, J. B. J. Chem. Soc., Perkin Trans.
1 1990, 345-351. (b) Korde, S. S.; Baig, M. H. A.; Desai, U. R.; Trivedi,
G. K. Steroids 1996, 61, 290-295.
10.1021/jo050217h CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/20/2005
J. Org. Chem. 2005, 70, 5313-5315
5313

SCHEME 1
SCHEME 2
Swern oxidation of epoxy alcohol 6 gave epoxy ketone
5 in very good yield (Scheme 6).12 With the suitably
substituted pinene ring system in hand, fragmentation
of the strained tricycle was investigated under a variety
of conditions. It was not clear at the outset of this study
whether the presence of the carbonyl group would inhibit
the key fragmentation reaction. Several previously re-
ported fragmentations relied on the formation of a
positive or partial positive charge on the carbon adjacent
to the cyclobutane ring to initiate the fragmentation
reaction.5a-g In our case, a positive or partial positive
charge would be destabilized by the adjacent carbonyl
group. Mineral acids,5a,b,f Hg(II) salts,5c and bases5i have
previously been employed in the ring opening of various
pinene-derived substrates. We surveyed basic, Bronsted,
and Lewis acidic and silylative conditions to effect the
fragmentation.
a
SCHEME 3
Under basic (tBuOK, LDA, KHMDS) or silylative
conditions (TMSOTf, TIPSOTf), only decomposition en-
sued. Under acidic conditions (Amberlite, AcOH,
CF3CO2H, H2SO4, HCl, HClO4) either decomposition or
no reaction was observed except in the case of concen-
trated HClO4. Treatment of epoxy ketone 5 with concen-
trated HClO4 afforded (R)-7-hydroxycarvone (2), albeit
in moderate (35%) yield. A survey of Lewis acids catalysts
(LiClO4, Hg(NO3)2, MgBr2, InCl3, Sm(OAc)3, NaBF4,
BF3‚Et2O) revealed that the optimal conditions for the
fragmentation (3 equiv of BF3‚Et2O, 0 °C) afforded
(R)-7-hydroxycarvone (2) in 50-55% yield on a multi-
gram scale. In all other cases either no reaction occurred
or complex product mixtures were obtained.
In conclusion, a convenient synthesis of (R)-7-hydroxy-
carvone (2) has been achieved in 3 steps in an overall
yield of 45% starting from inexpensive (S)-R-pinene on a
multigram scale. A modification of the Adam photooxy-
genation of R-pinene gave higher yield and fewer side
products and reduced the reaction time from 20 to 4.5 h.
a Reagents and conditions: (a) MCPBA, NaHCO3, CH2Cl2, 90%;
(b) LDA, ether, -78 °C, 85%; (c) MCPBA, NaHCO3, CH2Cl2, 90%;
(d) Ti(OiPr)4, CH2Cl2, rt, 80%.
surprising that Ti(OiPr)4 is capable of catalyzing the
hydride shift. Epoxy alcohols are frequently prepared by
Ti(OiPr)4-catalyzed oxidation of allylic alcohols without
competing rearrangement.10 Presumably Ti(OiPr)4 un-
dergoes ligand exchange with epoxy alcohol 6. The
epoxide would be activated toward ring opening upon
coordination with the internal Ti alkoxide. Epoxide ring
opening would then afford b-hydroxy ketone 8 after
hydrolysis of the alkoxide. Alleviation of strain between
the carbinol hydrogen and the methyl group on the
cyclobutane ring may be responsible for the facility of the
rearrangement.
Careful monitoring of the photooxygenation reaction
revealed that the rearrangement of epoxy alcohol 6 to
ketone 8 occurred before complete consumption of pinene.
Adam had noted in one case that a stepwise allylic
oxidation/oxygen transfer gave higher yield of the epoxy
alcohol than the one-step variant.6 We were able to both
increase the yield and eliminate the undesired rear-
rangement by employing a stepwise protocol wherein
complete photooxygenation of R-pinene (7) to hydro-
peroxide 11 was achieved prior to the introduction of
Ti(OiPr)4 (Scheme 5).11 The progress of the reaction was
Experimental Section
As complete 1H and 13C NMR data for compounds 5 and 6
have not previously been published, we provide full data below.
Hydroxyketone 87 (from epoxy alcohol 6). Ti(OiPr)4
(0.13 mL, 0.19 g, 0.67 mmol) was added to a solution of epoxy
alcohol 6 (1.0 g, 5.95 mmol) in CH2Cl2 (20 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature,
stirred for 1 h, then quenched by the addition of water (100 mL).
The mixture was filtered through a short Celite column, and
the organic layer was separated, dried over anhydrous MgSO4,
and concentrated in vacuo. The crude material was purified by
flash column chromatography on silica gel with 10/90 ethyl
acetate/hexanes to give hydroxy ketone 8 as a pale yellow oil
(0.79 g, 80%). Proton and 13C NMR data were fully consistent
with published data.7
1
monitored by H NMR analysis. Addition of a catalytic
amount (0.11 equiv) of Ti(OiPr)4 then led to the desired
epoxy alcohol 6 within 15 min without competing rear-
rangement. This one-pot, two-step protocol gave excellent
yield of epoxy alcohol 6 accompanied by a few percent of
allylic alcohol 10. On the basis of these results it is clear
that the modified Adam procedure could also be used to
access hydroxy ketone 8 in a one-pot process in high
yields. However, we did not optimize that transformation
since the focus of our investigation was the preparation
of 7-hydroxycarvone.
Epoxy Alcohol 6.6 Oxygen was bubbled into a solution of
S-(R)-pinene (7) (5.0 g, 36.7 mmol) and tetraphenylporphine
(TPP) (62 mg, 5 × 10-4 M) in CH2Cl2 (200 mL) in a photoreactor
at 0 °C under irradiation with a halogen lamp for 4 h. Irradiation
was discontinued and Ti(OiPr)4 (1.09 mL, 1.05 g, 3.7 mmol) was
introduced at 0 °C. Stirring was continued for 15 min before
quenching of the reaction mixture by the addition of water. The
solution was filtered through a short Celite column, and the
organic layer separated, dried over anhydrous MgSO4, and
(10) See, for example: Paquette, L. A.; Belmont, D. T.; Hsu, Y.-L.
J. Org. Chem. 1985, 50, 4667-4672. For a review, see: Katsuki, T.;
Martin, V. S. Org. React. 1996, 48, 1-299.
(11) Hydroperoxide 11 has previously been prepared and isolated:
Schenck, G, O.; Eggert, H.; Denk, E. Liebigs Ann. Chem. 1964, 19,
675.
(12) Epoxy ketone 5 has previously been prepared in 16% yield as
a mixture of diastereomers via epoxidation of the corresponding
enone: Meklati, B.; Bessiere-Chretien, Y. Bull. Soc. Chim. Fr. 1971,
8, 3133-3137.
5314 J. Org. Chem., Vol. 70, No. 13, 2005

SCHEME 4
(3 × 50 mL). The combined organic extracts were washed with
water, dried over anhydrous MgSO4, and concentrated in vacuo.
The crude material was purified by flash column chromatogra-
phy on silica gel with 10/90 ethyl acetate/hexanes to give epoxy
SCHEME 5
SCHEME 6
ketone 5 (1.7 g, 86%) as a pale yellow liquid: [R]23 +79.5
D
(c 1.71, CHCl3); IR (film) 1731 cm-1; 1H NMR (270 MHz, CDCl3)
δ 0.94 (s, 3H), 1.36 (s, 3H), 1.54 (d,1H), 1.81 (t,1H), 2.25
(m, 1H), 2.5-2.8 (m, 4H), 3.25 (d, 1H); 13C NMR (67 MHz, CDCl3)
δ 20.8, 26.0, 30.0, 38.5, 41.1, 42.6, 44.9, 53.9, 62.3, 208.2.
a
(R)-7-Hydroxycarvone (2). BF3‚Et2O (5.7 mL, 45 mmol) was
added dropwise to a solution of epoxy ketone 5 (2.5 g, 15 mmol)
in CH2Cl2 at 0 °C and stirred for 4 h at room temperature. The
reaction mixture was quenched by the addition of saturated
NaHCO3 solution. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried, concentrated, and purified
by flash chromatography on silica gel with CH2Cl2, followed by
5/95 methanol/CH2Cl2, to obtain (R)-7-hydroxycarvone (2)
(1.4 g, 55%) as a yellow liquid: [R]23D +36.9 (c 1.90, CHCl3); IR
(film) 3464,1655 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.74 (s, 3H),
2.3-2.8 (m, 5H), 4.25 (d, J ) 3.0 Hz, 2H), 4.76 (s, 1H), 4.82
(s, 1H), 6.93 (m, 1H); 13C NMR (67 MHz, CDCl3) δ 20.4, 30.9,
42.1, 43.1, 61.8, 110.8, 138.1, 145.8, 146.2, 200.3.
a Reagents and conditions: (a) DMSO, (COCl)2, NEt3, -78 °C;
(b) BF3‚OEt2, CH2Cl2, 0 °C.
concentrated in vacuo. The crude material was purified by flash
column chromatography on silica gel with 10/90 ethyl acetate/
hexane to give epoxy alcohol 6 (4.9 g, 92%) as a dark oil: [R]23
D
+4.05 (c 1.48, CHCl3); IR (film) 3506 cm-1; 1H NMR (270 MHz,
CDCl3) δ 0.81 (s, 3H), 1.3 (s, 3H), 1.5 (t, J ) 5.4 Hz, 1H), 1.9
(d, J ) 10.1 Hz, 1H), 1.96 (m, 2H), 2.15-2.35 (m, 2H), 2.5
(s, 1H), 2.8 (d, J ) 4.7 Hz, 1H), 2.95 (d, J ) 4.7 Hz, 1H), 3.9
(d, J ) 7.4 Hz, 1H); 13C NMR (67 MHz, CDCl3) δ 21.4, 25.7,
25.9, 33.3, 39.8, 41.3, 47.7, 57.0, 64.5, 66.1.
Acknowledgment. Support for this work was pro-
vided by NIH (RR-15569 and GM-59406) and Research
Corporation (CS-0674). M.C.M. is a Cottrell Scholar of
Research corporation.
Epoxy Ketone 5.12 A solution of DMSO (5.9 mL, 6.5 g, 83.2
mmol) in CH2Cl2 (10 mL) was added to a solution of oxalyl
chloride (3.1 mL, 4.5 g, 35.5 mmol) in CH2Cl2 (100 mL) at
-78 °C. After 5 min epoxy alcohol 6 (2.0 g, 11.9 mmol) in
CH2Cl2 (10 mL) was added dropwise followed after 10 min by
NEt3 (14.8 mL, 10.8 g, 107.1 mmol). The reaction mixture was
allowed to warm to room temperature and concentrated in vacuo.
The residue was dissolved in water and extracted with hexanes
Supporting Information Available: The 1H and 13C
NMR spectra of compounds 2, 5, 6, and 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050217H
J. Org. Chem, Vol. 70, No. 13, 2005 5315