New strategy toward the diverted synthesis of oxidized abietane diterpenes via oxidation of 6,7-dehydroferruginol methyl ether with dimethyldioxirane

Article abstract of DOI:10.1016/j.tetlet.2013.06.048

A series of oxidized abietane diterpenes have been synthesized from 8,11,13-abietanotriene. The reaction of 6,7-dehydroferruginol methyl ether with dimethyldioxirane (DMDO) was carried out under various conditions. In all cases, the oxidation of positions

Full text of DOI:10.1016/j.tetlet.2013.06.048

Tetrahedron Letters 54 (2013) 4479–4482
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New strategy toward the diverted synthesis of oxidized abietane
diterpenes via oxidation of 6,7-dehydroferruginol methyl ether
with dimethyldioxirane
b
a
b
I. Córdova-Guerrero a, , Lucía San Andrés , Alma E. Leal-Orozco , José M. Padrón ,
⇑
J. M. Cornejo-Bravo a, Francisco León c,d,
⇑
a Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California, Calzada Universidad, 14418, Parque Industrial Internacional, C.P. 22390 Tijuana,
Baja California, Mexico
b Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain
c Instituto de Productos Naturales y Agrobiología, CSIC, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Spain
d Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of oxidized abietane diterpenes have been synthesized from 8,11,13-abietanotriene. The reaction
of 6,7-dehydroferruginol methyl ether with dimethyldioxirane (DMDO) was carried out under various
conditions. In all cases, the oxidation of positions C-6 and C-7 were observed with high selectivity when
DMDO was used. When some reaction conditions, such as temperature and time were increased,
Received 7 May 2013
Revised 8 June 2013
Accepted 11 June 2013
Available online 18 June 2013
6a
-hydroxysugiol was obtained. Also an interesting formation of the cis aminol derivatives was synthe-
sized from cis epoxide 12.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Ferruginol
Sugiol
Dimethyldioxirane
Alkene oxidation
Dioxiranes are well known oxidants, that have been extensively
used to achieve a wide variety of functional group transforma-
tions.1 Dimethyldioxirane (DMDO) is used in common transforma-
tions such as epoxidation of alkenes,2 oxidations of alkynes,3 oxy-
functionalization of C–H bonds,4 oxidative cleavage of lactams,5
and reactions with heteroatoms possessing non-bonding electron
pairs, such as N, S, Se, and P.6
structure, led us to hypothesize that the oxygen functionality in
rings B and C might be responsible for their biological profile.
As part of our research program in the chemistry of diterpenes
and their structural modifications, herein we report a fast and sim-
ple route to generate abietane diterpenes oxygenated in the C-6
OH
C
OH
OMe
Abietane diterpenes are widely distributed in the natural
sources (Fig. 1). Representative examples are ferruginol (1), and
6-hydroxy-5,6-dehydrosugiol (2) isolated from the seeds of Cepha-
lottaxus harringtonia, which have exhibited important activities.7
The 6,7-dehydroferruginol methyl ether (3) is an antimicrobial
agent that has shown activity against methicillin-resistant Staphy-
lococcus aureus (MRSA) and vancomycin-resistant Enterococcus
15
11
20
1
14
2 A
B
7
4
O
6
H
H
OH
2
19
1
3
(VRE).8
6a-Hydroxysugiol (4), which was isolated from the cones
OH
OMe
O
of Sequoia sempervirens, has exhibited inhibition against colon,
lung, and breast human tumors.9 In addition, the sugiol methyl
ether (5), isolated from the bark of Juniperus formosana Hay, has
also exhibited interesting biological activity.8,10 The fact that these
metabolites exhibit similar biological activity and chemical
O
H
H
OH
4
5
⇑
Corresponding authors. Tel.: +1 6629152014; fax: +1 6629155638.
E-mail addresses: icordova@uabc.edu.mx (I. Córdova-Guerrero), jfleon.oyola@
Figure 1. Structure of naturally occurring abietane diterpenes. Ring lettering and
relevant atom numbering are shown for compound 1.
gmail.com, jfleon@olemiss.edu (F. León).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.048

4480
I. Córdova-Guerrero et al. / Tetrahedron Letters 54 (2013) 4479–4482
and C-7 positions with high selectivity, by means of diverse DMDO
oxidation conditions.
The synthesis started from the natural diterpene abieta-
8,11,13-triene 6 (Scheme 1), which was isolated from Salvia
clevelandii.11 Compound 6 was reacted with acetyl chloride in the
presence of aluminum chloride to afford ketone 7. Baeyer–Villiger
oxidation of 7 gave compound 8. A solution of the ester 3 and
methanol was treated with potassium carbonate to obtain the
known natural diterpene ferruginol 1, exhibiting spectroscopic
data identical to the natural sample. The reaction of 1 with lithium
hydroxide in DMF at 0 °C for 4 h afforded the corresponding lith-
ium salt, which was reacted with dimethyl sulfate12 at 0 °C for
45 min to give the aryl methyl ether 9. The synthesis of the alcohol
10 was achieved via oxidation of 9 with CrO3 in acetic acid, fol-
lowed by reduction of the ketone 5 with sodium borohydride in
methanol under inert atmosphere. The resulting diastereomeric
mixture of alcohols 10 was then transformed into methyl ether
11 by treatment with mesyl chloride in dry triethylamine at
0 °C.13 The spectral data of the unsaturated system 11 were in
complete agreement with those reported in the literature.14
As noted above, a short and efficient procedure was carried out
to prepare the key intermediate methyl ether 11 from natural
sources. Compound 11 was used as a suitable precursor to have ac-
cess to oxidized diterpenes through the functionalization of ring B.
It is widely known that DMDO is a reagent used in the epoxidation
of alkenes in a chemo- and stereoselective manner.15 Thus, we
investigated the scope of the oxidation of abietane diterpens with
DMDO. We followed the methodology used by Danishefsky15 to
obtain the unstable epoxide 12 in 80% yield. The epoxide was ob-
Figure 2. Selected NOESY correlations (double-ended arrows) of 13.
nucleophilic reaction with an amine on the less hindered face, pro-
vided the observed b-amine alcohols with high level of diastere-
oselectivity.18 It should occur via amine association with the
alkoxide and amine or via zinc binding to alkoxide and amine,
delivering the amine in a cis fashion.20
In order to set the optimal conditions to generate the epoxide
12, and taking into account the formation of the diol 15 in the pres-
ence of water, other derivatives were synthesized under slightly
modified conditions (Scheme 2). When the concentration of DMDO
was increased by an additional equivalent at ꢀ25 °C, the diol 15
yielded 70%. On the other hand, when the temperature, the num-
ber of equivalents of DMDO (8.5 equiv), and reaction times were
increased, the formation of a 3:1 mixture of 4 and 2, was observed
respectively. As a result, additional oxidation at C-6 and C-7 was
observed, in time dependent reaction, similar to what is expected
in acetylenic systems.3 The spectral data of compounds 4 and 2
were in agreement with those reported in the literature.
In conclusion, we are now reporting a simple route to obtain the
oxidized abietane diterpenes, similar to that of sugiol which holds
great pharmacological interest. DMDO is a convenient reagent for
the chemo- and stereoselective oxidation of abietane diterpenes
bearing a double bond in position C-6 and C-7. DMDO also repre-
sents a mild and effective reagent to provide various desired oxi-
dized derivatives. In addition, aminolysis of epoxide 12
represents an attractive route for the formation of b-amine alco-
hols. Mechanistic explorations are underway.
tained with high diastereoselectivity (a
:b ratio 20:1).16
It has been shown that epoxides such as compound 12 are very
sensitive to acid conditions and water.17 To further ascertain the
configuration of the epoxide 12, aminolysis was achieved with
ZnBr2 as the catalyst18 using 4-bromo aniline and 2-iodo aniline
to obtain two new b-amine alcohols 13 and 14 in 65% and 54%
yields respectively.19
The relative stereochemistry of 13 and 14 was determined by
the magnitude of the coupling constants and by ROESY experi-
ments. Thus, protons H-6 and H-7 showed correlation with
CH3-20, indicating a cis configuration between H-6 and H-7 in
the b-face (Fig. 2). The relative stereochemistry observed was sur-
prising at first sight, considering the high reactivity of the benzylic
position of C-7 and the possibility of electronic delocalization
generating a carbocation via opening of the epoxide. Further
O
O
O
OH
a
c
b
H
H
H
H
6
7
8
1
d
OMe
OMe
O
OMe
OMe
g
e
f
OH
H
H
H
H
11
10
5
9
Scheme 1. Reagents and conditions: (a) AcCl (5.5 equiv), AlCl3 (5 equiv), CH2Cl2, rt, 24 h, under N2, 92%; (b) m-CPBA (2.5 equiv), TsOH (0.1 equiv), ClCH2CH2Cl, reflux, 5 h, 81%;
(c) K2CO3 (3 equiv), MeOH/CH2Cl2 (2:1), 0 °C, 2 h, 89%; (d) LiOHꢁH2O (2 equiv), DMF, under N2, rt, 4 h, then (MeO)2SO2 (3 equiv), 0 °C, 45 min, 93%; (e) CrO3 (1.2 equiv), AcOH,
rt, 4 h, 63%; (f) NaBH4 (3 equiv), MeOH, rt, 12 h, under N2, 94%; (g) MsCl (2.5 equiv), Et3N (4 equiv), CH2Cl2, 0 °C, 12 h, under N2, 79%.

I. Córdova-Guerrero et al. / Tetrahedron Letters 54 (2013) 4479–4482
4481
OMe
OMe
OMe
c
b
NH
NH
Br
H
H
O
H
OH
OH
13
I
14
12
a
OH
OMe
OH
e
d
O
OH
H
H
H
OH
OH
4
11
15
f
4
2
+
Scheme 2. Reagents and conditions: (a) DMDO/acetone (0.08 M, 2 equiv), CH2Cl2, ꢀ25 °C, 1 h, 80%; (b) 4-Bromoaniline, ZnBr2, CH3CN, reflux, 15 h, 54%; (c) 2-Iodoaniline,
ZnBr2, CH3CN, reflux, 15 h, 65%; (d) (I). DMDO/acetone (0.08 M, 3 equiv), CH2Cl2, ꢀ25 °C 2 h, I(II). NaSEt, DMF, 90 °C, 8 h, 70%; (e) (I). DMDO/acetone (0.08 M, 8.5 equiv),
CH2Cl2, 25 °C, 20 min; II. NaSEt, DMF, 90 °C, 8 h, 70%; (f) I. DMDO/acetone (0.08 M, 8.5 equiv), CH2Cl2, 25 °C, 1 h, (II). NaSEt, DMF, 90 °C, 8 h, 60% for 4, 20% for 2.
11. Guerrero, I. C.; Andres, L. S.; Leon, L. G.; Machin, R. P.; Padron, J. M.; Luis, J. G.;
Acknowledgment
Delgadillo, J. J. Nat. Prod. 2006, 69, 1803–1805.
12. Abad, A.; Arno, M.; Domingo, L. R.; Zaragoza, R. J. Tetrahedron 1985, 41, 4937–
F.L. was supported in part by JAE-Doc Program from the Minis-
terio de Ciencia e Innovación, Spain.
4940.
13. Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Pollini, G. P.; Simoni, D.;
Zanirato, V. Tetrahedron 1988, 44, 6451–6454.
14. Gan, Y.; Li, A.; Pan, X.; Chan, A. S. C.; Yang, T. K. Tetrahedron: Asymmetry 2000,
11, 781–787.
A. Supplementary data
15. Stachel, S. J.; Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6785–6787.
16.
6a,7a
-epoxy-12-methoxy-ferruginol (12): 1H NMR (400 MHz, CDCl3): d 1.20 (6H,
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.06.048.
d, J = 6.9 Hz, Me-16 and Me-17), 1.22 (3H, s, Me-19), 1.24 (3H, s, Me-18), 1.30
(3H, s, Me-20), 3.25 (1H, sept, J = 6.8 Hz, H-15), 3.90 (3H, s, O-Me), 4.23 (1H, dd,
J = 4.7, 9.3 Hz, H-6), 4.76 (1H, d, J = 4.7 Hz, H-7), 6.66 (1H, s, H-11), 7.31 (1H, s,
H-14).
17. Cambie, R. C.; Grimsdale, A. C.; Rutledge, P. S.; Walker, M. F.; Woodgate, P. D.
Aust. J. Chem. 1991, 44, 1553–1573.
18. Pachón, L. D.; Gamez, P.; van Brussel, J. J. M.; Reedijk, J. Tetrahedron Lett. 2003,
44, 6025–6027.
References and notes
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19. General procedure for formation of b-amino alcohols. To a solution of crude
epoxide 12 (21 mg, 0.0668 mmol) in CH3CN were added 4-bromoaniline
(12.7 mg, 0.0715 mmol) and ZnBr2 (0.1 equiv). The reaction mixture was
refluxed for 15 h after which time it was concentrated under reduced pressure
and purified by silica column chromatography using hexane-AcOEt (3%), to
2. (a) Gervay, J.; Peterson, J. M.; Oriyama, T.; Danishefsky, S. J. J. Org. Chem. 1993,
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54, 515–517.
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yield compound 13 (21 mg) as a red solid; ½a D20
+63.0° (CHCl3, c 0.3); UV kmax
ꢂ
(log e) (EtOH) 354 (5.75) nm; IR mmax: 3384, 2957, 2927, 2360, 1715, 1595,
1497, 1463, 757 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.06 (3H, d, J = 6.6 Hz, Me-
;
16), 1.08 (3H, d, J = 6.6 Hz, Me-17), 1.09 (3H, s, Me-18), 1.17 (3H, s, Me-19),
1.25 (1H, m, H-3), 1.31 (3H, s, Me-20), 1.51 (1H, br d, J = 13.4 Hz, H-3), 1.70 (1H,
m, H-2), 1.84 (1H, m, H-2), 2.22 (1H, br d, J = 12.3 Hz, H-1b), 3.18 (1H, sept,
J = 6.8 Hz, H-15), 3.82 (3H, s, OMe), 4.30 (1H, dd, J = 5.2, 7.6 Hz, H-6b), 4.62 (1H,
d, J = 5.2 Hz, H-7b), 6.61 (2H, d, J = 8.7 Hz, H-20 and H-60), 6.74 (1H, s, H-11),
6.97 (1H, s, H-14), 7.27 (2H, d, J = 8.7 Hz, H-30 and H-50); 13C NMR (100 MHz,
CDCl3): d 19.0 (t, C-2), 22.2 (q, C-19), 22.5 (q, C-16), 22.7 (q, C-17), 23.4 (q, C-
18), 26.6 (d, C-15), 34.1 (s, C-4), 34.7 (q, C-20), 38.5 (t, C-1), 39.4 (s, C-10), 42.7
(t, C-3), 54.4 (q, OMe), 57.0 (d, C-5), 57.2 (d, C-7), 70.4 (d, C-6), 105.4 (d, C-11),
109.6 (s, C-40), 115.7 (d, C-20 and C-60), 125.1 (d, C-14), 126.3 (s, C-8), 132.0 (d,
C-30 and C-50), 134.8 (s, C-13), 147.3 (s, C-9), 147.7 (s, C-10), 156.4 (s, C-12);
EIMS m/z (rel. int.): 485 [Mꢀ1]+ (2), 467 (3), 330 (2), 314 (100), 299 (73), 271
(28), 257 (17), 229 (15),172 (28), 92 (10), 65 (10); HREIMS m/z: 485.1903
(calcd for C27H35NO2Br, 485.1929). Application of the same procedure using 2-
iodo aniline gave the compound 14 (18 mg) as yellow solid ½a D20
ꢂ +78.0° (CHCl3,
c 0.7); UV kmax (log e) (EtOH) 333 (6.35) nm; IR mmax: 3354, 2927, 1713, 1600,
1503, 1463, 1259 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.04 (3H, d, J = 6.9 Hz,
;
Me-16), 1.10 (3H, d, J = 6.9 Hz, Me-17), 1.16 (3H, s, Me-18), 1.19 (3H, s, Me-19),
1.33 (3H, s, Me-20), 2.20 (1H, m, H-1b), 3.19 (1H, sept, J = 6.8 Hz, H-15), 3.82
(3H, s, OMe), 4.33 (1H, dd, J = 5.4, 7.8 Hz, H-6), 4.62 (1H, d, J = 5.4 Hz, H-7), 6.48
(1H, dd, J = 1.4, 7.5 Hz, H-50), 6.65 (1H, d, J = 8.0 Hz, H-60), 6.75 (1H, s, H-11),
10. Kuo, Y. H.; Yu, M. T. Phytochemistry 1996, 42, 779–781.

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I. Córdova-Guerrero et al. / Tetrahedron Letters 54 (2013) 4479–4482
6.97 (1H, s, H-14), 7.16 (1H, dd, J = 1.4, 8.3 Hz, H-40), 7.72 (1H, d, J = 8.0 Hz, H-
147.6 (s, C-9), 150.3 (s, C-10), 156.8 (C-12); EIMS m/z (rel.int.): 532 [M-1]+ (2),
515 (1), 463 (6), 402 (1), 328 (20), 314 (100), 300 (22), 299 (84), 271 (35), 259
(13), 257 (28) 229 (20), 218 (13), 187 (5), 128 (5), 69 (10); HREIMS m/z:
532.1071 (calcd for C27H35NO2I, 532.1101).
30); 13C NMR (100 MHz, CDCl3): d 19.5 (t, C-2), 22.0 (q, C-19), 22.5 (q, C-16),
23.0 (q, C-17), 23.5 (q, C-18), 26.9 (d, C-15), 34.7 (s, C-4), 35.1 (q, Me-20), 38.9
(t, C-1), 39.8 (s, C-10), 43.5 (t, C-3), 54.9 (q, OMe), 57.6 (d, C-5), 57.9 (d, C-7),
71.1 (d, C-6), 105.6 (d, C-11), 109.5 (d, C-50), 111.0 (d, C-40), 115.9 (d, C-60),
116.0 (s, C-20), 125.8 (d, C-14), 127.3 (s, C-8), 132.8 (d, C-30), 135.3 (s, C-13),
20. Mahindaratne, M. P. D.; Fahmy, H. T. Y.; Garcia, J. A.; Negrete, G. R. Synth.
Commun. 2003, 33, 1391–1398.