Stereoselective trans-dihydroxylation of terpinen-4-ol: Synthesis of some stereoisomers of p-menthane-1,2,4-triol

Article abstract of DOI:10.1016/S0957-4166(02)00207-0

A high level of trans-stereoselectivity in the dihydroxylation of the homoallylic alcohol, terpinen-4-ol 1 (R=H) has been achieved. Thus, the enantiomeric triols 2a and 2b were separately synthesized in high yield and with high stereoselectivity by trans-

Full text of DOI:10.1016/S0957-4166(02)00207-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 915–918
Stereoselective trans-dihydroxylation of terpinen-4-ol: synthesis
of some stereoisomers of p-menthane-1,2,4-triol
Ioan Cristea,* Erika Kozma and Carmen Batiu
Department of Organic Chemistry, ‘Babes-Bolyai’ University, 11 Arany Janos Str. 3400 Cluj-Napoca, Romania
Received 1 April 2002; accepted 29 April 2002
Abstract—A high level of trans-stereoselectivity in the dihydroxylation of the homoallylic alcohol, terpinen-4-ol 1 (R=H) has
been achieved. Thus, the enantiomeric triols 2a and 2b were separately synthesized in high yield and with high stereoselectivity by
trans-dihydroxylation of the enantiomeric (4S)-terpinen-4-ol 1a (R=H), and (4R)-terpinen-4-ol 1b (R=H), respectively, using
hydrogen peroxide as oxidant and V2O5 as catalyst. In the same way, the enantiomeric triols 3a and 3b were obtained from the
enantiomeric (4S)-terpinen-4-yl tosylate 1a (R=tosyl) and (4R)-terpinen-4-yl tosylate 1b (R=tosyl), respectively. © 2002 Elsevier
Science Ltd. All rights reserved.
The trans-dihydroxylation of an alkene may be
achieved by its treatment with a suitable peroxycar-
boxylic acid, the reaction proceeding by initial cis addi-
tion to give an epoxide (oxirane), which undergoes
acid-catalyzed ring scission in an anti manner through
attack by the corresponding carboxylic acid, normally
present in the reaction medium, to give a mixture of
monoesters. Hydrolysis of the ester mixture then
affords in most cases a mixture of diastereomeric 1,2-
diols1–3 with stereochemistry resulting from overall
trans-addition to the alkene. Hydrogen peroxide can
also oxidize alkenes to diols trans-dihydroxylation with
the advantage that the free diols are obtained directly.
intermediates are epoxides, which readily undergo ring-
opening under acidic conditions. In our research we
investigated the stereoselectivity of the trans-dihydroxyl-
ation (via epoxidation) of the homoallylic alcohol, ter-
pinen-4-ol and some its derivatives using H2O2 as oxi-
dant and catalytic amounts of V2O5. We have found
that vanadium is a very efficient catalyst in this reac-
tion. V2O5 was reacted with H2O2 at 30°C for 20 min to
give a red solution of the active epoxidizing agent
peroxyvanadic acid.8 This epoxidizing agent was then
added to the reaction mixture. The reaction of terpinen-
4-ol with H2O2/V5+ gave the triol in better yield and
selectivity than with other transition-metal catalysts
(e.g. Mo, W). Both of these methods were far better
than the outcome when a peracid system was used (see
Table 1). It is well known that the rate of epoxidation
of allylic alcohols with hydroperoxides in the presence
Certain oxides, such as WO3,4,5 SeO2 and V2O5 react
with H2O2 to give unstable inorganic peroxy acids as
the reactive species and catalyze the oxidation. The
trans-stereochemistry of the addition suggests that the
6
7
Table 1. trans-Dihydroxylation of 1a with different oxidants and catalystsa
Oxidant
Catalyst
Productsb ratio 2a:3a
% Yield
% d.e.
Method Ref.
CH3COOH/H2O2
HCOOH/H2O2
CH3CN/H2O2
H2O2
H2O2
H2O2
72:28
76:24
80:20
75:25
90:10
97:3
32
30
52
25
81
87
44
52
60
50
80
94
12b,c
12b
(NH4)5H4[PMo6V6O40
Na2WO4
V2O5
)
a All stoichiometric reactions were carried out in acetone at a concentration of 1.34 M in each reagent and 0.007 M of catalyst; temp. 55°C, time
3 h.
b Analyzed by GC–MS.
* Corresponding author. Tel.: +40-64-193833; fax: +40-64-193818; e-mail: icristea99@yahoo.com
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00207-0

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I. Cristea et al. / Tetrahedron: Asymmetry 13 (2002) 915–918
of a vanadium catalyst is more than 1000 times the rate
of epoxidation of the parent alkene.9 In the cyclohexene
system the axial homoallylic hydroxyl group directs
epoxidation by coordination with the oxidizing agent in
the transition state.10 trans-Dihydroxylation of each
enantiomer 1a and 1b, (R=H) of terpinen-4-ol can
furnish two diastereoisomers: 2a (with trans diaxial
orientation for new hydroxyl groups) and 3a ( with
trans diequatorial orientation for new hydroxyl
groups), 2b and 3b, respectively (see Scheme 1).
gave the other enantiomer (1R,2R,4R)-p-menthane-
1,2,4-triol 2b. The literature12 contains some reports
concerning the synthesis of p-menthane-1,2,4-triols 2a
and 2b using peracetic and performic acids, but in very
low yield and selectivity (about 30% yield). In the
conformational analysis the bulky isopropyl group at
C(4) of the terpinen-4-ol is considered to be equatorial
and the 4-hydroxyl is in the more readily accessible
axial position. As shown in Scheme 2, the high stereose-
lectivity in the reaction of 1a can be attributed to the
strong coordination of the hydroxyl group to the highly
reactive epoxidizing agent, followed by intramolecular
oxygen transfer to the double bond of the homoallylic
alcohol. The epoxidation is stereoselective and takes
place from the face cis to hydroxyl, leading to
(1R,2S,4S)-1,2-epoxy-p-menthane-4-ol (cis-epoxide) as
the intermediate, which cannot be isolated and readily
undergoes ring-opening under acidic conditions. It is
well known that unsymmetrical epoxides tend to open
under acidic conditions at the more substituted carbon,
due to stabilization in the transition state of the partial
High yields and stereoselectivities have been observed
in the trans-dihydroxylation of terpinen-4-ol: thus,
(4S)-terpinen-4-ol11 (1a, R=H) was easily reacted with
H2O2/V5+ to give (1S,2S,4S)-p-menthane-1,2,4-triol 2a
in about 87% yield and 97% selectivity (see Table 2).
The reaction was performed at 55°C in acetone, with
stoichiometric amounts of alcohol and H2O2 at a con-
centration of 0.007 M V2O5 for 2 h and compound 2a
was obtained in 87% isolated yield. In the same man-
ner, (4R)-terpinen-4-ol 1b (R=H) stereospecifically
Scheme 1.
Table 2. Stereoselectivity in trans-dihydroxylation of 1a with H2O2/V5+
Starting materialsa
Temp. (°C)
Time (h)
Productsb ratio 2a:3a
% Yield
% d.e.
1a (R=H)
1a (R=acetyl)
1a (R=tosyl)
55
55
55
2
3
3
97:3
65:35
20:80
87
70
84
94
30
60
a Stoichiometric reactions were carried out in acetone at a concentration of 1.34 M in each reagent and 0.007 M of V2O5.
b Analyzed by GC–MS.

I. Cristea et al. / Tetrahedron: Asymmetry 13 (2002) 915–918
917
Scheme 2.
trans-Dihydroxylation of the (4S)-terpinen-4-yl tosylate
1a (R=tosyl) with H2O2/V5+ gave (1R,2R,4S)-p-men-
thane-1,2,4-triol 3a in much better yield (69%) and
diastereoselectivity (d.e.=80%) than in the reaction of the
acetate. The other diastereoisomer 2a was also obtained
as the minor product (15% yield and 20% diastereoselec-
tivity). In the tosylate 1a (R=tosyl), the tosyl group
remains in the axial position (conformational energies for
tosyl 0.50 kcal/mol and for isopropyl 2.21 kcal/mol)13 and
exerts steric hindrance on this face. Additionally, coordi-
nation with the epoxidizing agent is greatly diminished,
so the other face is less hindered and epoxidation takes
placetranstothetosylgroup, leadingtothestereoselective
formation of a trans-epoxide as intermediate. Nucle-
ophilic attack by water upon the protonated epoxide at
the more substituted C(1) center gives rise to the diaxially
disubstituted twist conformation of the cyclohexane ring
which must then subsequently invert to the diequatorially
disubstituted chair form of triol 3a, with trans-diequato-
rial orientation of the new hydroxyl groups. During the
reaction the tosyl group is lost. The reaction course for
the formation of 2a (ca. 15%) is best explained by attack
of a water molecule at the less substituted C(2) center,
but sterically hindered by the tosyl group from C(4), the
ring conformation changes smoothly from the half-chair
of the epoxide to the chair of triol 2a. In the same manner,
(4R)-terpinen-4-yl tosylate 1b, (R=tosyl) stereospecifi-
cally gave the other enantiomer (1S,2S,4R)-p-menthane-
1,2,4-triol 3b.
carbenium ion. Opening of cyclohexene oxides gener-
ally proceeds in such a fashion that the trans-diaxial
rather than the trans-diequatorial product is obtained
(Furst–Plattner rule).13 In our case, axial-attack of the
protonated epoxide at the more substituted carbon,
C(1), by a water molecule (SN2 mechanism) leads to
triol 2a where the two hydroxyl groups have trans-diax-
ial orientation. To confirm this hypothesis, the pure
cis-epoxide (prepared by the Payne method)14 was
allowed to react under the same conditions with H2O2/
V5+ and only the triol (1S,2S,4S)-2a was obtained in
90% yield. Also, we tried to selectively shield the b-face
(the same part with OH) and also reducing the coordi-
nation with the epoxidizing agent by esterification of
the hydroxyl group of terpinen-4-ol with acetyl and
tosyl groups: low stereoselectivity was observed in the
trans-dihydroxylation of terpinen-4-yl acetate and the
reaction of (4S)-terpinen-4-yl acetate 1a (R=Ac) with
H2O2/V5+ yielded a mixture of esters, which on alkaline
hydrolysis gave triols 2a and 3a in a ratio of 65:35 (see
Table 2). It is probable that the poor coordination of
the acetoxy group with the epoxidizing agent leads to a
mixture of two epoxides (cis and trans), which further
hydrolyze to the triols 2a and 3a. Very interesting
results were obtained in the trans-dihydroxylation of
terpinen-4-yl tosylate: in this case the other
diastereoisomer 3a was obtained in good yield and high
selectivity (see Scheme 3).
Scheme 3.

918
I. Cristea et al. / Tetrahedron: Asymmetry 13 (2002) 915–918
Representative procedure for trans-dihydroxylation
9. Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta
1979, 12, 63.
To a stirred suspension of vanadium pentoxide (0.05 g,
0.27 mmol) in acetone (5 mL), hydrogen peroxide (1
mL) was dropwise added at 30°C for 10 min. After 15
min. V2O5 goes promptly into solution to form blood
red peroxyvanadic acid. Acetone (20 mL) and (S)-(+)-
terpinen-4-ol (7.4 g, 47 mmol, 97% purity, 62% e.e.,
[h]D=+21, c=1) were then added to the reaction mix-
ture. The mixture was heated to 55°C and hydrogen
peroxide (4 mL of 35% solution, 47 mmol) was added
at a rate of 0.05 mL/min. via syringe pump. After the
addition was completed, the mixture was stirred at
55°C for an additional 1 h, the solvent then removed
under reduced pressure and the residue diluted with
water (30 mL). The white precipitate was filtered off,
washed with cold water (10 mL) and dried to yield a
crude product (7.6 g, 87% yield and 97% d.e., by
GC–MS analysis). Recrystallization from acetone gave
(1S,2S,4S)-p-menthane-1,2,4-triol 2a, 6.8 g, 77% yield)
as white needles with mp 173°C and [h]D=+24, (c=1.5,
EtOH) (lit.12a mp 174°C, [h]D=+36 (0.5, EtOH).16
10. For reviews on hydroxy-directed epoxidations, see: (a)
Sheldon, R. A. In Aspects of Homogeneous Catalysis;
Ugo, R., Ed.; D. Reidel: Dordrecht, 1981; Vol. 4, pp.
3–70; (b) Jorgensen, K. A. Chem. Rev. 1989, 89, 431–58;
(c) Sheldon, R. A. J. Mol. Catal. A 1995, 102, 23.
11. The absolute configuration of terpinen-4-ol was estab-
lished by: Ohloff, G.; Uhde, G. Helv. Chim. Acta 1965,
48, 10; (+)-terpinen-4-ol has (4S)-configuration and (−)-
terpinen-4-ol has (4R)-configuration.
12. (a) Hikino, Y. J. Pharm. Soc. Japan 1965, 85, 477; (b)
Garside, P.; Halsall, T. G.; Hornby, G. M. J. Chem. Soc.
1969, C5, 716; (c) Pailer, M.; Scheidl, O.; Gutwillinger,
H.; Klein, E.; Obermann, H. Monatsh. Chem. 1981, 112,
987.
13. Eliel, E. L. In Stereochemistry of Organic Compounds;
Wiley, S. H. I., Ed.; Wiley, 1994; p. 696, 730.
14. Frank, W. C. Tetrahedron: Asymmetry 1998, 9, 3745.
15. (a) Suga, T.; Von Rudloff, E. Can. J. Chem. 1969, 47,
3682; (b) Cristea, I.; Kozma, E. Studia Univ. ‘Babes-
Bolyai’, Chimia 2002, in press.
16. (1R,2R,4R)-p-Menthane-1,2,4-triol 2b, [h]D=−19.5 (c=
1.5 EtOH), lit.12c, [h]D=−21.7 (0.38, EtOH) was obtained
in pure form from (R)-(−)-terpinen-4-ol (97% purity, 58%
e.e., [h]D=−19 (c=1, EtOH). (S)-(+)-Terpinen-4-yl tosyl-
ate 1a, (R=tosyl) [h]D=+21, (c=1.5, EtOH) reacted in
the same manner to give a mixture of triols 2a and 3a,
(ratio 20:80 by GC–MS) which was chromatographed on
silica gel (CH2Cl2–acetone, 3:1) to afford 2a. Further
elution gave (1R,2R,4S)-p-menthane-1,2,4-triol 3a as col-
orless crystals. Recrystallization from acetone afforded
colorless prisms of 3a with mp 156°C and [h]D=+6.5
(c=1, EtOH). 1H NMR (DMSO-d6, 300 MHz): 4.05 (1H,
d, 7.5, C2OH), 3.78 (1H, s, C4OH), 3.55 (1H, s, C1OH),
3.22 (1H, dd, 11, 4.8, H2), 1.65 (1H, dd, 6.4, 4, H3eq), 1.58
(1H, dd, 6.5, 4.5, H6eq), 1.45 (1H, dd, 6.5, 4.5, H5eq), 1.38
(1H, hept, 7, H8), 1.29 (1H, dd, 6.2, 5, H3ax), 1.25 (1H,
dd, 14, 5.4, H6ax), 1.20 (1H, dd, 14, 5.4, H5ax), 1.08 (1H,
s, CH3), 0.83 (6H, d, 7, 2CH3). 13C NMR: 76.4 (C2), 74.6
(C1), 71.1 (C4), 31.8 (C7), 37.2 (C3), 35.4 (C6), 30.2 (C5),
27 (C8), 21.1 (C9), 20.8 (C10). MS, m/z (%):127 (50), 117
(35), 109 (46), 55 (62), 43 (100), 41 (52). Anal. calcd for
C10H20O3: C, 63.83; H, 10.63; found: C, 63.52; H,
10.27%. (1S,2S,4R)-p-Menthane-1,2,4-triol 3b, [h]D=
−5.5 (c=1.5, EtOH) was obtained in pure form from
(R)-(−)-terpinen-4-yl tosylate 1b, R=tosyl, [h]D=−17
(c=1.3, EtOH). Compounds 1a and 1b (R=acetyl, tosyl)
were synthesized by literature procedures.15a,b All specific
rotations were performed in EtOH at 20°C.
Acknowledgements
The authors gratefully acknowledge the Ministry of
Education and Research in Romania for the financial
support during the course of this research and the
Institute of Chemistry (Cluj-Napoca) for GC–MS
analyses.
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