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10009-3130/17/5304-0000 ©2017 Springer Science+Business Media New York
Chemistry of Natural Compounds, Vol. 53, No. 4, July, 2017
MULTI-STEP REARRANGEMENT MECHANISM FOR ACETYL
CEDRENE TO THE HYDROCARBON FOLLOWER†
S. K. Paknikar,1* F. S. Kamounah,2 P. E. Hansen,2
and M. S. Wadia3
Conversion of acetyl cedrene (2) to its follower (3) using acetic anhydride and polyphosphoric acid involves
a multi-step cationic molecular rearrangement, which is consistent with deuteriation and 1-13C labeling
studies of acetyl cedrene. The key step involves cyclopropylcarbinyl cation-cyclopropylcarbinyl cation
rearrangement.
Keywords:
α
-cedrene, deuterium exchange, acetylation, cyclopropylcarbinyl cation-cyclopropylcarbinyl cation
rearrangement (CCR).
Fragrance materials derived by the acetylation of the hydrocarbon fractions of cedarwood oils are commercially
available under different trade names. Acetyl cedrene (2) is one of the bulk fragrance materials [1, 2] with annual production
of over 2000 tons in the world. On a commercial scale, it is manufactured from the hydrocarbon fraction of cedarwood oil and
is of environmental concern because it is continuously released down the drain to aquatic systems [3, 4].
The acetylation of cedrene can lead to various products depending on the reaction conditions. Hansen and co-workers
[5] undertook a detailed study on the acetylation of cedarwood oil (Virginia) with (CH3CO)2O and polyphosphoric acid in
CH2Cl2, which leads, besides acetyl cedrene (2), also to a minor product, 1,7,7-trimethyl-2,3-(3′4′-dimethylbenzo)-
bicyclo[3.2.1]-octane (3), called the follower. This product is unambiguously identified by 2D NMR (HMBC, COSY) and
13C-labelling studies. Acetylation of cedrene (1) with (CH3CO)2O using TiCl4 as the catalyst gave acetyl cedrene (2), a vinyl
ether, and a hydroxyketone having a tricyclo[5.2.2.0]undecane skeleton [6].
1) Prof. S. C. Bhattacharyya Organic Synthesis Laboratory, VerGo Pharma Research, Verna, Goa 403722, India,
e-mail:skpakni@yahoo.co.in; 2) Department of Science and Environment, Roskilde University, P.O. Box 260, DK-4000,
Roskilde, Denmark; 3) Department of Chemistry, University of Pune, 411007, Pune, India. Published in Khimiya
Prirodnykh Soedinenii, No. 4, July–August, 2017, pp. 562–565. Original article submitted December 26, 2015.
Follower 3, label was found at C-(16)
a. PPA, Ac2O, EDC; b. 1-13C labeled Ac2O
Scheme 1. Acetyl cedrene and its follower. In the follower the numbers in brackets are the ones from acetyl cedrene.
†Dedicated to Prof. Sukh Dev on his 91st Birthday.
(1 6 )
H H
O
+
123
1
2
5
7
10 99
5
1
a
9
10
11
3' 12
13
5'
A
B
C
C
B
A
(1 )
(3 )
(5 )
(1 2 )
(1 3 )
(1 4 )
(7 ) (1 7 )
(1 5 )
(1 0 )
D
D
5'
3'
6'
3'
+
350% 50%
b
2
In the present study we report on the mechanism of formation of the follower 3 based on numerous rearrangements
involving ring expansion and ring contraction and leading to the structure of the follower (3).
The acetylation of cedarwood oil or
α
-cedrene (1) with 1-13C labelled (CH3CO)2O led to the follower (3) (Scheme 1)
containing the 13C label at C-3′. Deuterium labelling using TFAA and D2O resulted in incorporation of only one deuterium
atom shared equally between C-5′ and C-6′ (Scheme 1) of the follower. Acetyl cedrene-d4 and acetyl cedrene-d6 were also
isolated. Structural analysis of 3 (Scheme 1) shows that rings A, B, C of 2 are rearranged as B, A, C in follower 3. Formation
of 3 from 2 can only be explained by a multistep intramolecular rearrangement. Scheme 1 shows that sequentially: ring C of 2
has undergone initial ring enlargement and subsequent ring contraction; cleavage of the C6–C7 bond of 2 and formation of the
new C6–C2 bond; enlargement of ring A of 2 with concomitant loss of water.
We considered it useful to understand further the mechanistic features of this enigmatic transformation. The mechanism
for the formation of 3 from 2 when 1-13C labelled (CH3CO)2O was used is shown in Scheme 2.
One characteristic feature of the formation of the follower 3 is sluggish reaction rates. DFT calculation of B3LYP/6-31G*
type using the Gaussian version 09 (Gaussian) revealed that the first neutral intermediate III (Scheme 2) is higher in energy
than acetyl cedrene by ~20 kcal. A series of further cascade-like cationic rearrangements is involved with breaking and bond-
forming intermediates. The formation of the neutral intermediate III (Scheme 2) is supported by the observation that this
process is the reverse pathway for the biosynthesis of
α
-cedrene from farnesyl pyrophosphate, which has been established
previously [7]. Few other feasible mechanisms for the formation of follower 3 could be devised, and only the one presented in
Scheme 1 fits the observation of 13C enriched label at the C-3′ position of follower 3. Hence the key rearrangement is
cyclopropylcarbinyl cation-cyclopropylcarbinyl cation rearrangement (CCR) and is well known [8, 9]. During the deuteriation
of commercial acetyl cedrene, the follower was also deuterated, and it was observed that aromatic protons are exchanged.
Interestingly, the product was only monodeuterated (follower-d1) and the isotope was shared equally between the C-5′ and C-6′
positions of the follower 3 [5]. Scheme 3 shows the mechanism for the conversion of 2 into the monodeuterated follower. This
equal distribution of one deuterium atom between C-5′ and C-6′ can be accounted for by the facile 1,2-hydride and 1,2-deuteride
shifts and equilibration. Scheme 3 shows the acid-catalyzed conversion of acetyl cedrene-d3 to acetyl cedrene-d4 and acetyl
cedrene-d6.
The most characteristic feature of deuteration experiments was incorporation of a single deuterium atom distributed
equally between C-5′ and C-6′. It is possible to explain the equal distribution as being due to rapid 1,2-hydride and
1,2-deuteride shifts, as shown in Scheme 3.
HO
H
O
H
H+HO
+
OH
+
OH
OH
H+
III III IV
CCR*
VII VI V
+H
H
H
+i
ii
-H2O
3'
VIII IX 3
-H+
O
H+
Follower 3
i. 1,2-H– shift; ii. –H+
Scheme 2. Mechanism for the formation of follower 3 with location of 13C enriched at 3′.
i) The labeled 13C enriched carbon is C-3′. ii) cyclopropylcarbinyl cation-cyclopropylcarbinyl cation
rearrangement (CCR).
3
EXPERIMENTAL
Cedarwood oil (Virginia), D2O, polyphosphoric acid, and HPLC solvents were purchased from Sigma-Aldrich and
used as received. Acetic anhydride-1-13C (91.4%) was from Prochem (London). Column chromatography was carried out
using Merck Kieselgel 60 (0.015–0.040 mm). Mass spectra were obtained on an Agilent 7890A GC/5975 inert mass spectrometer.
PMR and 13C NMR spectra were recorded in CDCl3 with SiMe4 internal standard on a Varian Mercury 300 spectrometer.
Follower-d1. During the deuteration of commercial acetyl cedrene [5], the follower was also deuterated. The two
compounds were separated by flash chromatography on silica gel and with CH2Cl2 as eluent. The deuterated follower was
isolated (0.13 g), and from the PMR and 13C NMR spectra it was clear that the compound was a mixture of two isotopomers,
both monodeuterated.
Follower-13C. A mixture of polyphosphoric acid (1.2 g), acetic anhydride-1-13C (91.4%) (1.9 mL), CH2Cl2 (1.0 mL),
and cedarwood oil (Virginia, 1.0 mL) was stirred at 50°C under a nitrogen atmosphere for 4 days. After cooling, the mixture
was treated with ice water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with
water (3 × 10 mL) and brine (10 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure.
The recovered yellow oil residue (0.8 g) showed a mixture of acetyl cedrene (65%) and the follower (8%) by CC-MS, the rest
being isomers of acetyl cedrene.
Theoretical Calculations. The molecular geometries were optimized using the Gaussian 09 suite of programs
(Gaussian) of Density Functional Theory (DFT). A. Becke's functional [10] and C. Lee et al. [11] exchange correlation term
(B3LYP) and basis set 6-31G (d) were used [12].
A multistep mechanism consistent with our isotopic labeling studies (13C and 2H) for the conversion of acetyl cedrene
(2) to the follower (3) is presented. The key step consistent with these mechanistic studies is cyclopropylcarbinyl cation-
cyclopropylcarbinyl cation rearrangement (CCR). The present work adds value to terpene chemistry, a ubiquitous source of
exciting molecular rearrangements [13, 14].
DO DO
D
+
O
D
H
+
CCR
-H
+
H
O
H
D
+
TFA A
D
2
O
D
OD
+
D
OD
H
+
OD
D+
1,2-D
-
shift 1,2-H
-
shift
D
OD
H
H
D
+
D
OD OD
D
D
+
-H
+
+
H
H
H
D
+
H
H
H
D
-D
2
O-D
2
O
D
5'
D
6'
-H
+
-H
+
Follower 3 (D-6′) Follower 3 (D-5′)
Scheme 3. Mechanism for the formation of deuterated follower 3.
4
ACKNOWLEDGMENT
We express our deep gratitude to Prof. R. B. Bates and Prof. Mar Gomez Gallego for critical evaluation of the
proposed mechanisms and valuable suggestions, and Dr. Nitin Borkar, CEO, VerGo Pharma Research Laboratories Pvt. Ltd.,
Verna, Goa-403722, India for support.
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