Synthesis of (+)-perillyl alcohol from (+)-limonene

Article abstract of DOI:10.1016/j.tetlet.2014.01.039

(+)-Perillyl alcohol (1) has been synthesised in four steps and 39% overall yield from commercially available limonene oxide (4). The sequence features, as its key step, a palladium(0)-mediated transformation of a secondary allylic acetate (6) into its primary isomer (7). An application of (+)-perillyl alcohol (1) in a formal synthesis of naturally occurring (-)-mesembrine (2) and (-)-mesembranol was demonstrated.

Full text of DOI:10.1016/j.tetlet.2014.01.039

Tetrahedron Letters 55 (2014) 1431–1433
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Tetrahedron Letters
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Synthesis of (+)-perillyl alcohol from (+)-limonene
⇑
Kimberly Geoghegan, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
(+)-Perillyl alcohol (1) has been synthesised in four steps and 39% overall yield from commercially avail-
able limonene oxide (4). The sequence features, as its key step, a palladium(0)-mediated transformation
of a secondary allylic acetate (6) into its primary isomer (7). An application of (+)-perillyl alcohol (1) in a
formal synthesis of naturally occurring (ꢀ)-mesembrine (2) and (ꢀ)-mesembranol was demonstrated.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 November 2013
Revised 4 December 2013
Accepted 10 January 2014
Available online 18 January 2014
Keywords:
Monoterpene
Isomerisation
p-Allyl palladium complex
Overman rearrangement
The naturally occurring monoterpene (ꢀ)-perillyl alcohol (1)
represents a functionalised enantiopure molecule, which, along
with its corresponding aldehyde, has been employed as a ‘chiral-
pool’ starting material (Scheme 1).1 We have recently used (ꢀ)-1
to assemble (+)-2, the enantiomer of the naturally occurring Scele-
tium alkaloid, mesembrine.2
Since the enantiomer of perillyl alcohol is not currently
commercially available, a chemical method to prepare (+)-1 was
considered. A means to isomerise selectively the endocyclic, trisub-
stituted alkene present in (ꢀ)-1 is attractive in terms of efficiency
but is without direct precedent.3 Consequently, the inexpensive
monoterpene limonene [(+)-3] was identified as a potential mate-
rial to access (+)-1. Based on selectivity concerns the direct chem-
ical allylic functionalisation of (+)-3 was disregarded,4 although it
should be mentioned that a biotransformation using a modified
organism has been reported to perform the necessary allylic oxida-
tion converting (+)-3 into (+)-1.5
with LDA9 in THF at ꢀ78 °C, and following work-up, the allylic
alcohol 5 was isolated as a mixture of diastereoisomers (Scheme 2).
The secondary alcohol 5 was directly converted into acetate 6, un-
der standard conditions, which was isolated in good yield over the
two steps. According to a literature report concerning a related
compound, treatment of 6 with TMSBr was investigated.8 How-
ever, in our hands, none of the hoped for primary allylic bromides
(not shown) was formed. We therefore considered the use of p-al-
lyl transition metal chemistry to isomerise the epimeric allylic
acetoxy-functionality in 6 into its less-sterically encumbered pri-
mary isomer, 7. Although the use of acetoxy groups as nucleophiles
in
p-allyl palladium chemistry does not feature frequently in the
literature, several reports augured well for the success of the
proposed formal Claisen rearrangement.10 Pleasingly, after some
HO
OH
In terms of converting (+)-3 into (+)-1 the aim was to take
advantage of the differential reactivity between the endo- and
S
R
R
the exocyclic alkene, which enables mono-epoxide
4 to be
prepared.6 This compound is in fact also commercially available
as a mixture of cis- and trans-diastereoisomers7 and based on liter-
ature precedent,8,9 it was envisaged that a selective epoxide-allylic
alcohol transposition would access a functionalised handle, ulti-
mately facilitating the formation of (+)-1.
( )-1
Ref. 2
(+)-1
(+)-3
MeO
MeO
(2)
Key reactions:
NMe
(1) Overman rearrangement;
(2) Intramolecular Heck reaction
- Cyclic sulfonamide double
reduction; (3) Isopropenyl
oxidative cleavage
Thus, conversion of (+)-3 into 4 was performed with 0.9 equiv of
meta-chloroperbenzoic acid (m-CPBA) according to a literature
procedure (cis-4/trans-4; 60:40).6 This material was then treated
(1)
H
(3)
O
(+)-2
Scheme 1. Application of (ꢀ)-perillyl alcohol (1) in the synthesis of (+)-2 and the
proposed synthesis of (+)-1 from limonene (+)-3.
⇑
Corresponding author. Tel.: +353 17162291.
E-mail address: paul.evans@ucd.ie (P. Evans).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.039

1432
K. Geoghegan, P. Evans / Tetrahedron Letters 55 (2014) 1431–1433
OH
O
m-CPBA
RO
H
N
(i) Cl3CCN,
DBU, rt;
LDA, THF,
(0.9 equiv.),
Cl3C
(i) NaOH(aq), EtOH, rt;
CH2Cl2,
0 °C to rt
-78 °C, 93%
O
(ii) PhMe,
110 °C
(ii) ArSO2Cl, Et3N,
CH2Cl2, 0 °C to rt, 45%
(+)-3
4
R = H: 5
Ac2O, Py, CH2Cl2,
0 °C to rt, 97%
(+)-1
( )-8
R = Ac: 6
MeO
Br
H
OAc
OH
N
S
Ref. 2
MeO
Pd(PPh3)4 (1 mol%),
K2CO3,
( )-2
O2
THF, 110 °C,
(6:7; 35:65)
MeOH, rt,
43% (2 steps)
( )-9
(+)-1
7
Scheme 4. The Overman rearrangement of (+)-1: synthesis of (ꢀ)-9.
Scheme 2. Synthesis of (+)-perillyl alcohol (1) from (+)-limonene (3).
In summary, (R)-perillyl alcohol [(+)-1] was prepared in four
steps (39% overall yield) from commercially available (+)-limonene
oxide (4). The utility of (+)-1 was demonstrated in a formal synthe-
sis of natural mesembrine [(ꢀ)-2] by its four-step conversion into
sulfonamide (ꢀ)-9.
OH
OAc
Ac2O, Py,
CH2Cl2, 0 °C
to rt, 96%
Acknowledgements
( )-1
( )-7
[α]2D0 -81 (c = 2.0, CHCl3)
[α]2D0 -67 (c = 1.8, CHCl3)
The authors would like to thank University College Dublin for
financial support and the National University of Ireland for an
NUI Travelling Studentship (K.G.). Membership (P.E.) of COST ac-
tion CM0804 is acknowledged. Dr. Kamalraj V. Rajendran is
thanked for assistance with HPLC.
OAc
OH
Ac2O, Py,
CH2Cl2, 0 °C
to rt, 91%
(+)-1
[α]2D0 +84 (c = 1.8, CHCl3)
(+)-7
Supplementary data
[α]2D0 +69 (c = 2.7, CHCl3)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
039.
Scheme 3. Comparison of synthetic (+)-1 and its acetate (+)-7 with (–)-1 and (ꢀ)-7.
optimisation, it was found that the use of 1 mol % of Pd(PPh3)4 in
THF at 110 °C in a sealed tube led to the formation of 7 in 76% iso-
lated yield as an inseparable mixture of 7 and 6 (65:35). Attempts
to improve the isolated yield of 7, and also to drive the process to
completion with the inclusion of sodium acetate or tetra-n-butyl-
ammonium acetate (1–3 equiv), and by transferring the process
to a microwave apparatus, were found neither to improve the iso-
lated yield of 7 nor to alter dramatically the ratio between 7 and 6.
Basic hydrolysis of the thus obtained mixture of 7 and 6 gave
perillyl alcohol [(+)-1], which now proved separable from the cor-
responding secondary alcohol (5).11 The material thus isolated was
formed in 43% yield over the two steps, a figure reflecting that the
allylic acetate rearrangement does not proceed to completion.
Comparison between the specific rotation of commercial (S)-(ꢀ)-
1 and synthetic (R)-(+)-1 demonstrated approximately equal and
opposite values. Additionally, both enantiomers were converted
into their corresponding acetates, (S)-(ꢀ)-7 and (R)-(+)-7, and
again polarimetry supported the stereochemical assignments
(Scheme 3). Proton and carbon NMR spectra for both sets of enan-
tiomers also matched, however, unfortunately we were unable to
separate (ꢀ)-7 and (+)-7 by chiral GC (b-Dex column).
References and notes
1. For examples of the use of optically active perillyl alcohol and aldehyde, see:
(a) Tanner, D.; Andersson, P. G.; Tedenborg, L.; Somfai, P. Tetrahedron 1994, 50,
9135; (b) Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M. Angew. Chem., Int. Ed.
2008, 47, 7314; (c) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47,
6199; (d) Abe, H.; Sato, A.; Kobayashi, T.; Ito, H. Org. Lett. 2013, 15, 1298; For a
recent demonstration of a monoterpene-based synthesis, see: (e) Jøgensen, L.;
McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science
2013, 341, 878.
2. Geoghegan, K.; Evans, P. J. Org. Chem. 2013, 78, 3410.
3. Xu, Z.-B.; Qu, J. Chem. Eur. J. 2013, 19, 314.
4. Thomas, A. F.; Bucher, W. Helv. Chim. Acta 1970, 53, 770.
5. van Beilen, J. B.; Holtackers, R.; Lüscher, D.; Bauer, U.; Witholt, B.; Duetz, W. A.
Appl. Environ. Microbiol. 2005, 71, 1737.
6. Rodgriguez, R.; Ollivier, C.; Santelli, M. Tetrahedron Lett. 2004, 45, 2289.
7. Limonene epoxide has been used in the formal synthesis of mesembranol:
Evarts, J. B., Jr.; Fuchs, P. L. Tetrahedron Lett. 2001, 42, 3673.
8. Hanuš, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.; Mechoulam, R. Org.
Biomol. Chem. 2005, 3, 1116.
9. D’Souza, A. M.; Paknikar, S. K.; Dev, V.; Beauchamp, P. S.; Kamat, S. P. J. Nat.
Prod. 2004, 67, 700.
10. (a) Trost, B. M.; Verhoeven, T. R.; Fortunak, J. M.; McElvain, S. M. Tetrahedron
Lett. 1979, 20, 2301; (b) Grieco, P. A.; Takigawa, T.; Bongers, S. L.; Tanaka, H. J.
Am. Chem. Soc. 1980, 102, 7587; (c) Oehlschlager, A. C.; Mishra, P.; Dhami, S.
Can. J. Chem. 1984, 62, 791; (d) Deardorff, D. R.; Myles, D. C.; MacFerrin, K. D.
Tetrahedron Lett. 1985, 26, 5615; (e) Deardorff, D. R.; Shambayati, S.; Linde, R.
G.; Dunn, M. M. J. Org. Chem. 1988, 53, 189; (f) Park, J. B.; Ko, S. H.; Kim, B. G.;
Hong, W. P.; Lee, K.-J. Bull. Korean Chem. Soc. 2004, 25, 27.
As shown in Scheme 4, synthetic (+)-perillyl alcohol (1) was
subjected to an Overman rearrangement sequence, which initially
gave (ꢀ)-8, that was subsequently converted into sulfonamide (ꢀ)-
9. Since an identical strategy involving (+)-9 was used for the
synthesis of (+)-2 and its related alcohol (+)-mesembranol, this se-
quence represents a formal synthesis of the naturally occurring
alkaloids mesembrine [(ꢀ)-2] and (ꢀ)-mesembranol.2
11. Synthetic procedure: Under N2, a mixture of acetate 6 (300 mg, 1.55 mmol, 1
equiv) and Pd(PPh3)4 (18 mg, 0.016 mmol, 1 mol %) in anhydrous THF (3.2 mL)
was heated in
a
sealed glass pyrex tube for 15 h (oil bath
temperature = 110 °C). Once cooled, Et2O (10 mL) and H2O (10 mL) were
added and the layers separated. The aqueous layer was extracted with Et2O
(2 ꢁ 10 mL) and the combined ethereal layers washed with brine (10 mL) and
dried (MgSO4). The crude product, obtained after filtration and solvent
removal, was purified by column chromatography (c-Hex/EtOAc, 9:1) to
yield (R)-perillyl acetate [(+)-7] (228 mg, 76%) as a light orange oil which also
contained 6 (7:6; 65:35). [Rf = 0.5 (c-Hex/EtOAc, 6:1); IR (KBr, neat): 2933,
Compound (ꢀ)-9, thus obtained from (+)-1, was compared with
its enantiomer [(+)-9]2 by polarimetry and also chiral HPLC,12 both
of which served to further confirm the absolute stereochemistry of
synthetic (+)-1.
1741, 1654, 1373, 1240, 1024 cmꢀ1
CH), 4.73–4.70 (m, 2H, CH2), 4.44 (s, 2H, CH2), 2.19–2.02 (m, 4H, CH, CH2), 2.06
;
1H NMR (CDCl3, 400 MHz): d 5.73 (s, 1H,

K. Geoghegan, P. Evans / Tetrahedron Letters 55 (2014) 1431–1433
1433
(s, 3H, CH3), 1.99–1.92 (m, 1H, CH2), 1.87–1.81 (m, 1H, CH2), 1.72 (s, 3H, CH3),
1.53–1.45 (m, 1H, CH2); 13C NMR (CDCl3, 100 MHz): d 170.9 (CO), 149.6 (C),
132.6 (C), 126.1 (CH), 108.8 (CH2), 68.6 (CH2), 40.9 (CH), 30.5 (CH2), 27.2 (CH2),
26.5 (CH2), 21.1 (CH3), 20.7 (CH3)]. A solution of 7 (220 mg, 1.13 mmol, 1 equiv)
in MeOH (10 mL) was treated with K2CO3 (156 mg, 1.7 mmol, 1.5 equiv) and
the reaction mixture was stirred at room temperature and monitored by TLC.
On completion, most of the MeOH was removed under reduced pressure before
CH2Cl2 (10 mL) and H2O (10 mL) were added. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2 ꢁ 10 mL). The combined
organic layers were dried over MgSO4, filtered and concentrated to give the
crude alcohol, which was purified by flash column chromatography (c-Hex/
EtOAc, 6:1) to yield (R)-perillyl alcohol [(+)-1] (100 mg, 43% from 6) as a light
yellow oil. Rf = 0.2 (c-Hex/EtOAc, 3:1);
þ 84 (c 1.8, CHCl3) [(ꢀ)-1:
ꢀ 81 (c 2.0, CHCl3)]; IR (KBr, neat): 3332, 2923, 1646, 1451, 1436,
1053 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 5.70 (br s, 1H, CH), 4.78–4.67 (m, 2H,
CH2), 4.01 (s, 2H, CH2), 2.23–2.03 (m, 4H, CH, CH2), 1.99–1.89 (m, 1H, CH2),
1.87–1.82 (m, 1H, CH2), 1.74 (s, 3H, CH3), 1.54–1.44 (m, 1H, CH2); 13C NMR
(CDCl3, 100 MHz): d 149.9 (C), 137.4 (C), 122.6 (CH), 108.8 (CH2), 67.4 (CH2),
41.3 (CH), 30.6 (CH2), 27.6 (CH2), 26.3 (CH2), 20.9 (CH3).
½ ꢂ
a 2D0
½ ꢂ
a 2D0
;
12. HPLC analysis for (+)- and (ꢀ)-9: (IC column), n-heptane/EtOH; gradient elution
90:10 to 50:50 (1.0 mL/min): (ꢀ)-9 tr = 22.95 min, (+)-9 tr = 24.62 min.