Synthesis, stereochemistry and absolute configuration of deodarols and deodarones

Article abstract of DOI:10.1016/S0957-4166(01)00521-3

The stereochemistry and absolute configuration of the four deodarols 3 and two deodarones 4 derived from (R)-(+)-limonene 1 is described.

Full text of DOI:10.1016/S0957-4166(01)00521-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2947–2953
Synthesis, stereochemistry and absolute configuration of
deodarols and deodarones
Margarita B. Villecco,a Luis R. Herna´ndez,a Marcelo I. Guzma´n,a Ce´sar A. N. Catala´n,a,*
Mar´ıa A. Buciob and Pedro Joseph-Nathanb
aInstituto de Qu´ımica Orga´nica, Facultad de Bioqu´ımica, Qu´ımica y Farmacia, Universidad Nacional de Tucuma´n, Ayacucho 471,
San Miguel de Tucuma´n, 4000 Argentina
bDepartamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado 14-740, Mexico D.F. 07000, Mexico
Received 9 September 2001; accepted 30 October 2001
Abstract—The stereochemistry and absolute configuration of the four deodarols and two deodarones derived from R-(+)-limonene
is described. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
deodarols 3 and the two possible deodarones 4
obtained synthetically from (R)-(+)-limonene, as is
shown in Scheme 1.
The widely studied sesquiterpene constituents of the
Cedrus deodara Loud1–4 essential oil appear to derive
from cis-farnesyl pyrophosphate1 either by a 1,6-
cyclization to give bisabolane derivatives, or a 1,11-
cyclization, to give himachalane or longibornane
derivatives. Atlantones are the major sesquiterpene
ketones of this essential oil and its characteristic wood
odor is due to deodarones 4, which are present as
approximately 2% of the oil.1 This oil is also interesting
from a medicinal point of view owing to its anti-inflam-
matory activity against various experimental models of
inflammation.5
2. Results and discussion
The synthetic pathway involved the selective metalla-
tion of (R)-(+)-limonene 1 which was condensed with
senecialdehyde to give the corresponding atlantols 2,
which in turn were converted into deodarols 3 by a
mercuration–demercuration-catalyzed cyclization. As
the metallation of optically active limonene occurs
without altering the C(4)9 stereogenic center, four
diastereoisomeric deodarols 3a–d and subsequently, two
diastereoisomeric deodarones 4a and 4b were obtained.
The four diastereomeric deodarols 3a–d were obtained
in a 18:36:25:21 ratio and were readily separated by
reverse phase high pressure liquid chromatography
(RP-HPLC).
Deodarones 4 are tetrahydropyranyl sesquiterpenes
originally isolated from the wood of C. deodara.1 They
have been prepared synthetically by several methods
although, in all cases, as diastereoisomeric mixtures.6,7
Consequently, there are no data published for the indi-
1
vidual deodarones and the H NMR data reported for
the mixture of diastereomers have been only partially
assigned.8 On the other hand, deodarols 3 have not yet
been found in nature and have never been obtained
synthetically. As part of our synthesis of deodarones,
we have prepared and characterized each diastereoiso-
meric deodarol 3a–d. Herein, we report the preparation
and absolute configuration of the four possible
1
The H NMR spectra of the four deodarols 3 showed
the C(11)H signal around l 4.1 as a triple-triplet (J=
11.0, 4.5 Hz) evidencing that the hydroxyl group was
equatorial in the four diastereoisomers. W-Type cou-
plings between C(10)Heq and C(12)Heq were also evi-
1
dent in the H NMR spectra of the four deodarols. The
critical assignments of C(10) and C(12) were easily
made using the HMBC contour as are shown in Figs.
* Corresponding author. Tel.: (54-381) 424-7752 ext. 285; fax: (54-
381) 424-8025; e-mail: ccatalan@unt.edu.ar
1
2–4 for deodarols 3a–c. The total H and 13C NMR
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00521-3

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M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
Scheme 1. Synthetic pathway for the preparation of deodarols and deodarones.
assignments (Tables 1 and 2) were made with the aid of
spin–spin decoupling, COSY, NOESY, DEPT, HET-
COR, and HMBC experiments.
man projections by looking through the C(4)/C(8) bond
(see Fig. 1) reveals that only isomer 3b has a different
neighborhood for C(3), with the oxygen in an anti-posi-
tion. Following a similar reasoning and observing the
C(5) chemical shift, it can be seen that 3a is the only
isomer having the oxygen in an anti-position to C(5). It
therefore follows that (4R,8S,11S)- and (4R,8R,11R)-
configurations can be assigned to 3a and 3b, respec-
tively. In addition, oxidation of 3a and 3c gave a single
deodarone 4a, while oxidation of 3b and 3d gave the
other deodarone 4b. These results indicated that the
pairs of diastereoisomeric deodarols 3a/3c and 3b/3d
had the same configuration at C(8) and, therefore, 3c
and 3d have the (4R,8S,11R)- and (4R,8R,11S)-
configurations, respectively.
Two conformations of the tetrahydropyran ring, both
having the hydroxyl group in an equatorial disposition
are possible, i.e. a chair- or boat-like conformation.
Molecular modeling, using the PCMODEL10 program,
were performed to calculate the minimum energy con-
formation of each deodarol 3a–d, the results being
depicted in Fig. 1.
The 13C NMR spectra of the four deodarols 3a–d were,
as expected, very similar (Table 2). However, careful
evaluation of the chemical shifts for C(3) and C(5) of
each stereoisomer reveals that C(5) in 3a and C(3) in 3b
are shifted downfield some 2.4 ppm in comparison to
the remaining three compounds. Evaluation of New-
The absolute configuration at C(11) of the four
deodarols (3a–d) was further confirmed by the prepara-

M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
2949
Figure 1. Minimal energy conformation of deodarols and C(4)–C(8) bond Newman projections.

2950
M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
tion of their Mosher esters11 as shown in Tables 3 and
1
4 where the H NMR chemical shifts differences for
selected signals in the spectra of the (R)- and (S)-a-
methoxy-a-(trifluoromethyl)phenylacetate ester derived
from each deodarol are compared.
Figure 4. HMBC contour of Me-9, Me-14, and Me-15 region
of deodarol 3c.
Deodarones 4a and 4b were obtained by oxidation of
the respective deodarols. These deodarones have identi-
cal retention time in gas chromatography using a 30 m
HP-5 column. However, their mass spectra consistently
show slight differences in the relative abundance of the
ions at m/z 119, 120, 121, 134, and 141. Thus, in 4a the
ion at m/z 121 was always of lower intensity than its
neighbors of essentially identical intensity at m/z 134,
120, and 119, while in 4b the same occurred with the
ion at m/z 134 in relation to the ions at m/z 121, 120,
and 119. The 1H and 13C NMR data of each
diastereoisomer are given in Tables 5 and 6, respec-
tively. The assignments were made with the aid of
DEPT, HSQC experiments, and by comparison with
the corresponding deodarol spectra.
Figure 2. HMBC contour of Me-9, Me-14, and Me-15 region
of deodarol 3a.
It is interesting to note that natural deodarone was
claimed3 to be a mixture of two diastereoisomers hav-
ing the same configuration at C(4) supported by the
similarity of the natural deodarone specific rotation
value ([h]D=ca. +6) and that of the deodarone
obtained by the hydration of trans-atlantone. However,
the essential oil from C. deodara mainly contains trans-
atlantone,2 the possible biogenetic precursor of
deodarone, in near-racemic form.9 These facts, along
with the [h]D values measured in this work for
deodarones 4a and 4b of +46.3 and +67.0, respectively,
are indicative that natural deodarone and the
deodarone described in Ref. 3 is a mixture of the four
possible stereoisomers with a slight excess of the posi-
tive antipodes.
Figure 3. HMBC contour of Me-9, Me-14, and Me-15 region
of deodarol 3b.

M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
Table 1. 1H NMR data for deodarols 3a–da,b
2951
H
3a
3b
3c
3d
2
3
5.41
2.16
1.95
1.78
1.74
1.27
1.96
1.63
1.11
2.29
1.16
4.06
1.89
1.34
1.25
1.27
5.36
1.94
1.72
1.89
2.05
1.28
1.94
1.65
1.09
2.18
1.13
4.05
1.91
1.30
1.27
1.27
5.37
2.09
1.80
1.48
1.92
1.22
1.96
1.63
1.19
1.80
1.22
4.13
1.91
1.19
1.25
1.21
5.36
2.03
1.78
1.48
1.88
1.21
1.95
1.63
1.18
1.73
1.20
4.13
1.90
1.18
1.24
1.19
br d (4.2)
m
m
dddd (11.2, 11.2, 4.0, 2.0)
ddd (12.0, 5.1, 2.2)
dddd (12.0, 12.0, 12.0, 4.8)
m
4
5eq
5ax
6
7
9
10eq
10ax
11
12eq
12ax
14
br s
s
ddd (13.0, 4.5, 2.1)
dd (13.0, 11.0)
tt (11.0, 4.5)
ddd (12.3, 4.5, 2.1)
dd (12.3, 4.5)
s
15
s
a 300 MHz, CDCl3, TMS as internal standard.
b J values are the same for the four diastereoisomers.
3. Experimental
(hexane–EtOAc 9:1) to yield a mixture of the four
diastereoisomeric deodarols 3 (1.3 g, 40%). This mix-
ture was separated by HPLC using a C-18 column,
MeOH–H2O 72:28 as solvent, and a flow of 2.5 mL
min−1 to give 3a (tR 18.5 min, 213 mg), 3b (tR 20.7 min,
414 mg), 3c (tR 29 min, 296 mg), and 3d (tR 32.8 min,
245 mg):
For separations, a Gilson HPLC machine with refrac-
tive index detector was used. The column employed was
a Beckmann C-18 (5m, 10×250 mm). Retention times
(tR) were measured from the solvent peak. 1H, 13C,
COSY-1H/1H, HMBC and HSQC spectra: Mercury
300. H measured at 300 MHz, 13C at 75.4 MHz, TMS
1
as internal standard, solvent CDCl3. IR spectra:
Perkin–Elmer 16F PC FT-IR spectrophotometer. Spe-
cific rotations: Perkin–Elmer 241 or Horiba SEPA-300
polarimeters. Column chromatography (CC) Merck sil-
ica gel, particle size 0.040–0.063 mm (230–400 mesh,
ASTM). (R)-(+)-Limonene, n-butyllithium in hexane,
N,N,N%,N%-tetramethylethylenediamine (TMEDA), and
3-methyl-2-butenal were commercially available
(Aldrich). The concentration of active n-butyllithium
was checked using the 4-biphenylmethanol method.12
TMEDA was dried immediately prior to use by distilla-
tion from calcium hydride.
3.2.1. (4R,8S,11S)-Deodarol 3a. [h]589 +98.3, [h]578
+102.2, [h]546 +115.9, [h]436 +196.3, [h]365 +302.9 (c 1.36,
CHCl3). IR (CHCl3) wmax 3608, 3016, 1522, 1376, 1206.
EIMS 70 eV m/z (rel. int.): 187 (1), 164 (2), 159 (1), 146
(5), 143 (56), 131 (8), 125 (73), 119 (9), 107 (34), 95 (16),
1
87 (45), 85 (12), 79 (13), 67 (14), 57 (16), 43 (100). H
and 13C NMR data in Tables 1 and 2, respectively.
3.2.2. (4R,8R,11R)-Deodarol 3b. [h]589 +13.3, [h]578
+13.8, [h]546 +15.9, [h]436 +28.0, [h]365 +46.4 (c 3.97,
CHCl3). IR (CHCl3) wmax 3608, 3452, 3014, 1522, 1376,
1206. EIMS 70 eV m/z (rel. int.): 220 [M−H2O]+ (0.5),
3.1. Atlantols 2
Table 2. 13C NMR data for deodarols 3a–da
n-Butyllithium (0.025 mol), TMEDA (0.025 mol) and
(R)-(+)-limonene (0.05 mol) were reacted as in Ref. 9 to
give atlantols 2 (3.3 g, 60%, based on n-butyllithium).
Spectroscopic data were in agreement to those
reported.9
C
3a
3b
3c
3d
1
2
3
4
5
6
7
8
133.5
121.2
26.3
42.0
25.9
31.4
23.2
78.0
26.2
42.3
63.4
46.3
73.1
29.0
33.6
134.5
120.6
28.5
40.6
23.3
30.9
23.3
77.9
25.3
43.0
63.1
46.5
72.9
28.6
34.1
133.8
120.8
26.1
46.8
23.3
31.1
23.2
76.7
24.5
41.3
63.8
46.6
72.7
28.6
33.5
133.8
120.8
26.0
46.8
23.4
31.1
23.3
76.5
23.8
41.8
63.9
46.5
72.7
28.5
33.5
3.2. Deodarols 3
A mixture of atlantols 2 (3 g), Hg(AcO)2 (9.5 g), H2O
(14 mL) and THF (14 mL) was magnetic stirred
overnight at room temperature. A solution of aqueous
NaOH (3 M, 20 mL) followed by a solution of NaBH4
(700 mg) in aqueous NaOH (3 M, 20 mL) were added
and the mixture stirred 0.5 h after which the mixture
was saturated with NaCl and extracted twice with ethyl
ether. The combined ethereal phases were washed with
water, dried and evaporated. The residue (2.9 g) was
purified by column chromatography over silica gel
9
10
11
12
13
14
15
a 75.4 MHz, CDCl3, TMS as internal standard.

2952
M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
1
Table 3. Selected H NMR chemical shift values for (R)- and (S)-MTPA esters of 3a and 3b
H
3a
3b
(R)-MTPA
(S)-MTPA
DlR-S
(R)-MTPA
(S)-MTPA
DlR-S
9
1.05
2.26
1.35
1.97
1.64
1.29
1.26
1.12
2.32
1.44
1.90
1.54
1.28
1.20
−0.07
−0.06
−0.09
+0.07
+0.10
+0.01
+0.06
1.10
2.31
1.40
1.94
1.53
1.31
1.23
1.05
2.22
1.29
1.99
1.59
1.33
1.27
+0.05
+0.09
+0.11
−0.05
−0.06
−0.02
−0.04
10a
10b
12a
12b
14
15
1
Table 4. Selected H NMR chemical shift values for (R)- and (S)-MTPA esters of 3c and 3d
H
3c
3d
(R)-MTPA
(S)-MTPA
DlR-S
(R)-MTPA
(S)-MTPA
DlR-S
9
1.28
1.89
1.47
1.95
1.35
1.33
1.20
1.27
1.87
1.43
2.08
1.50
1.34
1.23
+0.01
+0.02
+0.04
−0.13
−0.15
−0.01
−0.03
1.25
1.75
1.43
2.02
1.37
1.32
1.21
1.26
1.82
1.47
1.94
1.34
1.31
1.18
−0.01
−0.07
−0.04
+0.08
+0.03
+0.01
+0.03
10a
10b
12a
12b
14
15
Table 5. 1H NMR data for deodarones 4a and 4ba,b
Table 6. 13C NMR data for deodarones 4a and 4ba
H
4a
4b
C
4a
4b
2
5.38
2.10
1.98
1.86
1.79
1.59
1.98
1.65
1.22
2.56
2.29
2.43
1.31
1.31
5.36
1.95–2.10
1.79
1.93
1.95–2.10
1.60
1.95–2.10
1.65
1.21
2.54
2.23
m
m
m
1
2
3
4
5
6
7
8
133.9
120.5
26.3
46.0
23.8
31.0
23.3
78.4
26.1
47.0
209.3
51.4
74.2
30.7
33.2
134.1
120.4
26.5
45.9
23.6
31.0
23.3
78.4
25.4
47.7
209.3
51.6
74.3
30.7
32.2
3a
3b
4
5a
5b
6a,b
7
dddd (12.0, 12.0, 5.5, 2.2)
m
m
m
br s
s
d (15.6)
d (15.6)
9
9
10a
10b
12a,b
14
15
10
11
12
13
14
15
2.42
1.30
1.30
s
s
s
a 300 MHz, CDCl3, TMS as internal standard.
b J values are the same for the two diastereoisomers.
a 75.4 MHz, CDCl3, TMS as internal standard.
3.2.4. (4R,8R,11S)-Deodarol 3d. [h]589 +46.6, [h]578
+48.2, [h]546 +54.3, [h]436 +91.1, [h]365 +145.5 (c 2.24,
CHCl3). IR (CHCl3) wmax 3620, 3016, 1522, 1376, 1210.
EIMS 70 eV m/z (rel. int.): 220 [M−H2O]+ (1), 187 (2),
164 (5), 159 (2), 146 (11), 143 (46), 131 (16), 125 (68),
119 (18), 107 (33), 95 (21), 87 (45), 85 (15), 79 (14), 67
187 (1), 164 (2), 159 (1), 146 (5), 143 (72), 131 (8), 125
(93), 119 (9), 107 (40), 95 (17), 87 (54), 85 (15), 79 (13),
1
67 (15), 57 (18), 43 (100). H and 13C NMR data in
Tables 1 and 2, respectively.
1
(16), 57 (17), 43 (100). H and 13C NMR data in Tables
3.2.3. (4R,8S,11R)-Deodarol 3c. [h]589 +75.0, [h]578
+78.2, [h]546 +89.0, [h]436 +151.9, [h]365 +239.8 (c 3.37,
CHCl3). IR (CHCl3) wmax 3608, 3452, 3014, 1522, 1374,
1206. EIMS 70 eV m/z (rel. int.): 220 [M−H2O]+ (1),
187 (2), 164 (6), 159 (2), 146 (12), 143 (45), 131 (18), 125
(71), 119 (20), 107 (34), 95 (22), 87 (45), 85 (15), 79 (15),
1 and 2, respectively.
3.3. (R)- and (S)-MTPA esters of deodarols
A solution of each of the deodarols 3a–d (10 mg, 42
mmol) in CH2Cl2 (2 mL) was treated with a solution of
dicyclohexylcarbodiimide (78 mg, 0.38 mmol), 4-
1
67 (16), 57 (16), 43 (100). H and 13C NMR data in
Tables 1 and 2, respectively.

M. B. Villecco et al. / Tetrahedron: Asymmetry 12 (2001) 2947–2953
2953
(dimethylamino)pyridine (11.6 mg, 95 mmol) and either
(R)- or (S)-a-methoxy-a-trifluoromethyl)phenylacetic
acid (38.8 mg, 0.17 mmol) in CH2Cl2 (2 mL), at room
temperature for 24 h. The mixture was concentrated
and the residue was suspended in EtOAc (3 mL),
successively washed with aqueous HCl (10%, 1 mL),
H2O, saturated aqueous NaHCO3 (1 mL) and brine,
dried over Na2SO4 and evaporated at reduced pressure.
In each case, the Mosher esters were purified by flash
column chromatography on silica gel using hexane–
EtOAc (33:1) as eluent.
(22), 93 (15), 85 (32), 83 (100), 79 (14), 77 (10), 67 (16),
55 (15), 43 (48), 41 (11).
Acknowledgements
The work in Tucuma´n was supported by grants from
CONICET (Argentina) and Consejo de Investigaciones
de la Universidad Nacional de Tucuma´n (CIUNT).
Partial financial support from CoNaCyT (Me´xico) and
stimulating support from CYTED (Spain) is also
acknowledged.
3.4. Deodarones 4
References
To a stirred suspension of pyridinium chlorochromate
(37 mg, 0.17 mmol) in anhydrous CH2Cl2 (0.5 mL) a
solution of deodarol (24 mg, 0.10 mmol) in CH2Cl2 (0.5
mL) was added. After 1.5 h, dry Et2O (1.0 mL) was
added and the supernatant liquid was decanted from a
black gummy residue. The residue was washed with dry
Et2O (3×0.5 mL). The combined organic solution was
percolated through a short pad of Florisil and the
solvent was evaporated. In each case, the deodarone
was purified by flash column chromatography on silica
gel using hexane–EtOAc (33:1) as eluent. Yield 87–91%.
1. Shankaranarayanan, R.; Krishnappa, S.; Bisarya, S. C.;
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3.4.1. (4R,8S)-Deodarone 4a. [h]680 +34.1, [h]650 +38.0,
[h]600 +44.2, [h]589 +46.3, [h]577 +48.2, [h]546 +53.3, [h]492
+64.2 (c 3.48, CHCl3). IR (CHCl3) wmax 3016, 1712,
1378. MS (EI) m/z: 236 (M+, 1), 218 (2), 162 (15), 141
(68), 134 (24), 121 (22), 120 (25), 119 (25), 105 (16), 95
(22), 93 (15), 85 (32), 83 (100), 79 (14), 77 (10), 67 (16),
55 (15), 43 (48), 41 (11).
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10. Burket, U.; Allinger N. L. Molecular Mechanics; ACS
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11. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90,
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Sa´nchez, J. S. J. Org. Chem. 1983, 48, 2603–2606.
3.4.2. (4R,8R)-Deodarone 4b. [h]680 +47.6, [h]650 +52.7,
[h]600 +63.2, [h]589 +67.0, [h]577 +70.6, [h]546 +79.6, [h]492
+102.2 (c 4.28, CHCl3). IR (CHCl3) wmax 3016, 1712,
1380. MS (EI) m/z: 236 (M+, 1), 218 (2), 162 (13), 141
(78), 134 (18), 121 (22), 120 (22), 119 (21), 105 (14), 95