Unexpected oxidation of ortho-phenol groups of carnosol with m-chloroperbenzoic acid

Article abstract of DOI:10.1055/s-2002-33513

The oxidation reaction of carnosol (2) with m-chloroperbenzoic acid and sodium bicarbonate in dichloromethane gave an abietane diterpene (3) with an anhydride function on C ring. The conversion can be rationalized by a Baeyer-Villiger reaction from the initially generated ortho-quinone. The structure of this anhydride was confirmed by spectroscopic and X-ray crystallographic analysis. This reaction could be an important key step towards the synthesis of natural products such us drimane sesquiterpenes.

Full text of DOI:10.1055/s-2002-33513

LETTER
1517
Unexpected Oxidation of ortho-Phenol Groups of Carnosol with m-Chloro-
perbenzoic Acid
U
nexpecte
o
d
O
xidation
a
of ortho-Ph
q
enol
G
roups
u
of
C
arnosolín G. Marrero, Lucía San Andrés Tejera,* Javier G. Luis, Matías L. Rodríguez
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2,
38206 La Laguna, Tenerife, Canary Islands, Spain
Fax +34(922)318571; E-mail: landrest@ull.es
Received 28 June 2002
complex. p-Quinone and muconic acid derivative forma-
Abstract: The oxidation reaction of carnosol (2) with m-chloroper-
tion have been observed, but the yields have generally
been low.
benzoic acid and sodium bicarbonate in dichloromethane gave an
abietane diterpene (3) with an anhydride function on C ring. The
In previous papers14,15 and on the basis of the isolation and
conversion can be rationalized by a Baeyer–Villiger reaction from
the initially generated ortho-quinone. The structure of this anhy-
chemical behaviour16 of a large number of abietane diter-
dride was confirmed by spectroscopic and X-ray crystallographic
penes from the Salvia species, we have postulated a bio-
analysis. This reaction could be an important key step towards the
synthetic pathway to highly oxidized abietatriene
synthesis of natural products such us drimane sesquiterpenes.
diterpenes in which 6,7-didehydrocarnosic acid, enzymat-
ic dehydrogenation processes and the participation of sin-
glet oxygen appear to play an important role. The
participation of a perepoxide intermediate in such a bio-
Key words: oxidation, natural products, abietatriene diterpenes,
rearrangement, ring expansion
synthetic pathway was proved by us through intramolecu-
Organic peracids are versatile reagents capable of oxidiz-
lar trapping experiments17 from 6,7-didehydrocarnosic
ing a variety of functional groups under generally mild
acid derivatives in which rosmanol and isorosmanol de-
conditions.1 Peracids react with olefins,2 amines,3 ke-
rivatives were isolated and characterized.
tones,4 sulfides,5 and a number of other functional
groups.1 In addition, their solubility in organic solvents,
ease of handling, and commercial availability make these
reagents particularly attractive for the oxidation of organ-
ic compounds.
However, attempts to obtain rosmanol and isorosmanol
from the natural diterpene carnosol (2), via epoxidation of
the intermediate (1) (Scheme 1) by treatment with solid
NaHCO3 and MCPBA in CH2Cl2 at room temperature
gave the unexpected product (3) as a white solid
(Scheme 2).
The physical and spectroscopical18 data of (3) including
HMBC analysis did not permit an unambiguous determi-
nation of its structure, and final evidence for (3) as 11,12-
seco-11,12-epoxy-11,12-dioxo-8,13-abietadien-20,7 -
olide was obtained from an X-ray analysis (Figure 1).19
Peracids react slowly with alcohols under ordinary condi-
tions.6,7 Indeed the reaction with alcohols is slow enough
to enable peracid mediated conversions of other function-
al groups in a molecule to be conducted without prior pro-
tection of the alcohol.8 However, in the presence of
catalytic amounts of nitroxide radicals9,10 or mineral ac-
ids,11,12 secondary alcohols and benzylic alcohols can be
rapidly and efficiently oxidized to ketones by m-chloro-
perbenzoic acid (MCPBA), although the oxidation of phe-
nols has not been reported under these conditions.
Hydroxylation appears to be an important result of reac-
tions between peroxy acids and many aromatic com-
pounds. Normally the oxidation of phenolic systems by
peroxyacetic acid produces p-benzoquinones and mucon-
ic acid derivatives. Apparently, initial para and ortho hy-
droxylation are followed by further oxidation to the para
quinones and the muconic acid respectively.13 Baeyer–
Villiger reaction generally requires longer reaction times
or higher temperatures and employs stronger peracids
than are necessary for the alcohol oxidations.
From investigations carried out on peroxy acid oxidations
of phenolic systems, it is clear that these reactions are
Figure 1 Molecular structure and atomic numbering for com-
pound 3
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1517,1519,ftx,en;D09302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1518
J. G. Marrero
LETTER
HCO3
H
OH
O
O
HO
HO
HO
OOC
OOC
Na
Na
O
NaHCO3(s)
O
CH2Cl2
r.t.
H
H
H
H
(1)
(2)
HCO3
OH
m-CPBA
HO
O
a)
OH
O
HO
H
O
OH
H
rosmanol
O
b)
OH
O
a)
HO
O
b)
O
H
OH
isorosmanol
Scheme 1
OH
O
When carnosol (2) was treated with freshly prepared
Ag2O in diethyl ether it gave ortho-quinone (5), which, on
treatment with MCPBA and NaHCO3 in CH2Cl2, yielded
the anhydride (3). On the other hand when carnosol (2)
was treated only with MCPBA in CH2Cl2 we obtained a
single product which was identified as ortho-quinone
(5).21 Finally when we changed the base for other buffers
generally employed in the Baeyer–Villiger reaction we
obtained the same anhydride (3). This experimental evi-
dence supports the process depicted in Scheme 4.
O
O
HO
O
O
NaHCO3
O
O
m-CPBA/ CH2Cl2
H
H
(3)
(2)
Scheme 2
O
MeOOC
MeOOC
O
O
O
O
OH
O
MeI, K2CO3
Me2CO, r.t.
HO
O
O
O
O
O
H
(3)
m-CPBA
H
(4)
O
O
NaHCO3
CH2Cl2
H
H
Scheme 3
(5)
(2)
Methylation of (3) with MeI and K2CO3 in acetone gave
the diester (4)20 (Scheme 3) which showed a molecular
ion at m/z = 390.2041 [M+] corresponding to a molecular
formula C22H30O6 and the 1H NMR spectrum showed ad-
ditional signals for two methoxy groups at = 3.75 and
3.77 ppm.
m-CPBA
O
Ar
O
O
O
H
O
O
O
O
H
O
O
It is well known that peroxy acids normally form anhy-
drides when reacted with 1,2-dicarbonyl compounds in in-
ert solvents or carboxylic acids in alkaline or acidic
media. Thereby the formation of anhydride 3 can be ex-
plained by a process shown in Scheme 4, in which the for-
mation of ortho-quinone (5) is the key to the process.
O
Baeyer-Villiger
O
H
(3)
Scheme 4
Synlett 2002, No. 9, 1517–1519 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Unexpected Oxidation of ortho-Phenol Groups of Carnosol
1519
(19) A. L. Spek, PLATON. A multipurpose crystallographic tool,
Utrecht University, Utrecht, Netherlands(2001).
It is important to note that, in our case, we never observed
the formation of the corresponding p-quinone from the
hydroxylation in C-14. On the other hand the reaction de-
scribed in this paper could be important in the synthesis of
other natural products such us the drimane sesquiterpenes.
Crystallographic Data for (3): Colourless irregular shaped
crystals, C20H48O5, Mw = 344.4, monoclinic system, space
group P21, Z = 2, a = 6.530(2) Å, b = 11.034(3) Å,
c = 12.705(3) Å, = 103.76(2)º, V = 889.1(4) Å3, Dc = 1.29
gcm–3, F(000) = 368, (MoK ) = 0.09 mm–1. The intensity
data of all unique reflections within the range 2.5–26.3º
were collected at r.t. on an Enraf-Nonius CAD4
Acknowledgement
diffractometer, using MoK radiation and graphite
We thank to FEDER (Grants Nº IFD 97-0602 and IFD 97-073-C02-
01) for financial support.
monochromador. Three standard reflections monitored
every 2 h of X-ray exposure showed no significant decay of
the intensity. A total of 1260 unique reflections were
recorded of which 592 were considered as observed under
F0>4 (F0). The intensities were corrected for Lorentz and
polarization factors, but no absorption correction was made.
The structure was solved by direct methods using
References
(1) (a) House, H. O. In Modern Synthetic Reactions, 2nd ed;
Benjamin W. A., Menlo park: California, 1972, Chap. 6,
292. (b) Hawkins, E. G. E. In Organic Peroxides; Van
Nostrand: Princeton New Jersey, 1961, Chap. 6, 161.
(2) Swern, D. Chem. Rev. 1949, 45, 1.
(3) Craig, J. C.; Purushothaman, K. K. J. Org. Chem. 1970, 35,
1721.
(4) Palmer, B. W.; Fry, A. J. Am. Chem. Soc. 1970, 92, 2580.
(5) Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem. 1970, 35,
2106.
(6) Tokumaru, K.; Simamura, O.; Fukuyama, M. Bull. Chem.
Soc. Jpn. 1962, 35, 1673.
(7) Gruselle, M.; Tichy, M.; Lefort, D. Tetrahedron 1972, 28,
3885.
(8) Miyashita, M.; Yoshikoshi, A. J. Am. Chem. Soc. 1974, 96,
1917.
(9) Cella, J. A.; Kelley, J. A.; Kenehan, E. F. J. Org. Chem.
1975, 40, 1860.
(10) Garem, B. J. Org. Chem. 1975, 40, 1998.
(11) Cella, J. A.; McGrath, J. P. Tetrahedron Lett. 1975, 4115.
(12) Kim, H. R.; Jung, J. H.; Kim, J. N.; Ryu, E. K. Synth.
Commun. 1990, 20(5), 641.
(13) Farrand, J. C.; Johnson, D. C. J. Org. Chem. 1971, 36, 3606.
(14) González, A. G.; San Andrés, L.; Aguiar, Z. E.; Luis, J. G.
Phytochemistry 1992, 31, 1297.
(15) González, A. G.; Aguiar, Z. E.; Grillo, T. A.; Luis, J. G.
Phytochemistry 1992, 31, 1691.
(16) González, A. G.; Aguiar, Z. E.; Ravelo, A. G.; Luis, J. G.
Tetrahedron 1989, 45, 5203.
SHELXS86, refinement was performed with SHELXL93,
using full-matrix least squares with anisotropic thermal
parameters for all the non-H atoms. The H-atoms were
placed in idealized positions and added in the last steps of the
refinement as a fixed isotropic contribution. The refinement
converged at R1 = 6.06% and wR2 = 18.23%, with a
goodness of fit for F2 of 1.01, the largest peak on the final
difference map was 0.22 e/Å3. Crystallographic data of(3),
including atomic coordinates, have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nº CCDC 188402. Copies of the data can be
obtained free of charge on applications to the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (Fax:
+44(1223)336033, e-mail: deposit@ccdc.cam.ac.uk).
(20) 11,12-Seco-8,13-abietadien-20,7 -lacton-11,12-dioic
Acid Dimethyl Ester (4): UV (EtOH): 246 nm. IR (CHCl3):
2924, 1754, 1722, 1242, 1091, 1031 cm–1. 1H NMR (300
MHz, CDCl3): = 0.83 (3 H, s, Me-19), 0.88 (3 H, s, Me-18),
1.08 (3 H, d, J = 7.0 Hz, Me-16), 1.09 (3 H, d, J = 7.0 Hz,
Me-17), 2.47 (1 H, bd, J = 14.2 Hz, H-1 ), 2.74 (1 H, hept,
J = 6.8 Hz, H-15), 3.75 (3 H, s, –OCH3), 3.77 (3 H, s,
–OCH3), 5.00 (1 H, s, H-7), 6.22 (1 H, s, H-14). 13C NMR
(75 MHz, CDCl3): = 18.3 (t, C-2), 19.2 (q, C-18), 21.4 (q,
C-16), 21.5 (q, C-17), 26.9 (t, C-1), 28.0 (t, C-6), 31.8 (q, C-
19), 32.6 (d, C-15), 34.2 (s, C-4), 40.5 (t, C-3), 45.4 (d, C-5),
47.2 (s, C-10), 52.0 (t, 2 –OCH3), 75.9 (d, C-7), 123.8 (d,
C-14), 136.8 (s, C-9), 142.0 (s, C-8), 144.0 (s, C-13), 165.1
(s, C-11), 168.8 (s, C-12), 174.2 (s, C-20). MS (EI): m/z
(%) = 390 (11) [M+], 347 (24), 331 (100), 299 (29), 255 (44),
211 (10), 69 (15). HRMS (EI): m/z = 390.2041 (calcd for
C22H30O6: 390.2042).
(21) 11,12-O-Didehydrocarnosol (5): UV (EtOH): 207 nm. IR
(CHCl3): 2960, 1750, 1665, 1462, 1109, 1029, 755 cm–1. 1H
NMR (300 MHz, CDCl3): = 0.87 (3 H, s, Me-19), 0.89 (3
H, s, Me-18), 1.12 (6 H, d, J = 7.0 Hz, Me-16, Me-17), 1.23
(1 H, m, H-3), 1.53 (1 H, bd, J = 13.3 Hz, H-3 ), 1.65 (2 H,
overlapping signal, H-2, H-5), 1.87 (1 H, dt, H-2 ), 1.97 (1
H, m, H-6), 2.20 (1 H, m, H-6 ), 2.30 (1 H, td, J1 = 4.6 Hz,
J2 = 14.0 Hz, H-1 ), 2.68 (1 H, bd, J = 14.4 Hz, H-1 ), 2.97
(1 H, hept, J = 7.0 Hz, H-15), 5.19, 5.20 (1 H, dd, J1 = 1.4
Hz, J2 = 4.0 Hz, H-7), 6.67 (1 H, s, H-14). 13C NMR (75
MHz, CDCl3): = 18.2 (t, C-2), 19.3 (q, C-18), 21.3 (q,
C-16), 21.3 (q, C-17), 27.0 (t, C-1), 27.8 (t, C-6), 27.8 (d,
C-15), 32.0 (q, C-19), 34.4 (s, C-4) 40.5 (t, C-3), 44.8 (d,
C-5), 48.7 (s, C-10), 76.4 (d, C-7), 129.6 (d, C-14), 135.6 (s,
C-9), 151.1 (s, C-13), 173.3 (s, C-20), 176.2 (s, C-11), 179.2
(s, C-12). MS (EI): m/z (%) = 328 (5) [M+], 284 (43), 215
(100), 204 (17), 165 (14), 141 (14), 55(20). HRMS (EI):
m/z = 328.1696 (calcd for C20H24O4: 328.1675).
(17) Luis, J. G.; San Andrés, L.; Fletcher, W. Q. Tetrahedron
Lett. 1994, 35, 179.
(18) 11,12-Seco-11,12-epoxi-11,12-dioxo-8,13-abietadien-
20,7 -olide(3): Mp: 226–228 °C; UV (EtOH): 207, 258 nm.
IR (CHCl3): 3440, 2962, 1744, 1725, 1290, 1112, 1046, 757
cm–1. 1H NMR (300 MHz, CDCl3): = 0.86 (3 H, s, Me-19),
0.90 (3 H, s, Me-18), 1.19 (3 H, d, J = 7.0 Hz, Me-16), 1.20
(3 H, d, J = 7.0 Hz, Me-17), 1.28 (1 H, dd, J1 = 3.2 Hz,
J2 = 13.1 Hz, H-3), 1.60 (3 H, overlapping signal, H-2, H-3 ,
H-5), 1.87 (3 H, overlapping signal, H-1 , H-2 , H-6), 2.15
(1 H, m, H-6 ), 2.68 (1 H, bd, J = 13.3 Hz, H-1 ), 2.97 (1 H,
hept, J = 7.0 Hz, H-15), 5.15 (1 H, dd, J1 = 1.5 Hz, J2 = 4.0
Hz, H-7), 6.37 (1 H, s, H-14). 13C NMR (75 MHz, CDCl3):
= 18.1 (t, C-2), 19.2 (q, C-18), 21.0 (q, C-16), 21.4 (q, C-
17), 25.7 (t, C-6), 31.8 (q, C-19), 33.0 (d, C-15), 34.5 (s, C-
4), 40.3 (t, C-3), 44.8 (d, C-5), 47.9 (s, C-10), 76.6 (d, C-7),
124.0 (d, C-14), 134.6 (s, C-9), 144.6 (s, C-8), 147.4 (s, C-
13), 155.6 (s, C-11), 160.7 (s, C-12), 172.7 (s, C-20). MS-
FAB: m/z (%) = 345 (14) [M+], 317 (6), 299 (20), 289 (11),
139 (13), 133 (41), 89 (24), 77 (11). HRMS-FAB: m/z =
345.1690 (calcd for C20H25O5: 345.1702).
Synlett 2002, No. 9, 1517–1519 ISSN 0936-5214 © Thieme Stuttgart · New York