Fluorination of kaurenoic acid derivatives by remote functionalization

Article abstract of DOI:10.1055/s-1999-2852

Kauranoids and related tetracyclic diterpenoids have recently shown an increasing interest because of the discovery of new biological activities that can be modified by the introduction of a fluorine atom. In this article it is described the stereospecific fluorination of the kauranols 6 and 7 by remote functionalization at the 'unactivated' C-7 position.

Full text of DOI:10.1055/s-1999-2852

LETTER
1429
Fluorination of Kaurenoic Acid Derivatives by Remote Functionalization
Josefa Anaya, Ma Concepción Grande, Manuel Grande,* Ana-Isabel Patino, Pascual Torres†
Departamento de Química Orgánica, Universidad de Salamanca, E-37008 Salamanca, Spain. Facultad de Ciencias, UNED, Elche, Alicante,
Spain.
Fax +34 23 294574; mgrande@gugu.usal.es
Received 3 June 1999
In memory of Professor Joaqu’n de Pascual Teresa.
12
13
Abstract: Kauranoids and related tetracyclic diterpenoids have re-
cently shown an increasing interest because of the discovery of new
biological activities that can be modified by the introduction of a
fluorine atom. In this article it is described the stereospecific fluori-
nation of the kauranols 6 and 7 by remote functionalization at the
"unactivated" C-7 position.
17
20
R16
11
1
14
7
9
16
2
3
10
H 8
H
5
4
R15
R15
H
H
6
18
CO2R
CO2Me
19
Key words: fluorination, kauranoids, natural products, synthetic
methods, terpenoids.
R15
R16
R
R15
1
2
H
H
H
6
7
α-OH β-Me
α-OH α-Me
Me
The interest in kaurane diterpenoids has recently in-
creased as some of them display various biological activ-
ities such as antimicrobial, antiinflammatory, anti-HIV,
cytotoxic, antifertility, insect antifeedant, etc.1 Kaura-
noids are also known to be the biological precursors of
gibberellins, growth regulation plant hormones, and some
of them have also shown gibberellin-like activity.1,2 We
reported in a recent paper the growth regulating activity of
thirteen tetracyclic diterpene derivatives related to kaura-
noic acid which were isolated from several Spanish Elae-
oselinum species.3 In that study we observed that some of
the tested substances were as active as or more active than
gibberellic acid, GA3. It was also concluded that the 7-hy-
droxykauranoids showed an increase of the gibberellin-
like activity, so it seemed interesting to introduce a func-
tional group at C-7 in natural kauranoids lacking in func-
tionalization on the B ring.
3
5
Me
Me
α-OH
8
9
=O
=O
β-Me
α-Me
=O
10 β-OH β-Me
11 β-OH α-Me
12
Me β-OH
CHO
7
+
6
9
8
11
10
(iv)
(v)
4
(iii)
(iii)
(i)
(ii)
(v)
1
2
3 + 4 + 5
12
Synthesis of kauranols 6, 7, 10 and 11: (i) CH2N2, Et2O, room temp.;
(ii) SeO2 (1.2 mmol), tBuOOH (1.5 mmol), CH2Cl2, room temp.; (iii)
H2 (1.3 atm.), Pd(10%)/C, EtOH, room temp.; (iv) PDC (2.7 mmol),
MeOH, CH2Cl2, room temp.; (v) NaBH4 (0.5 mmol), THF/EtOH
(95:5), 0° C.
As part of a project on the transformation and synthesis of
kauranoids and gibberellin analogues we report here our
findings in the study of remote functionalization at C-7 in
a tetracyclic diterpenoid skeleton. As starting material we
selected kaurenoic acid 1, major metabolite (40%) from
the hexane extract of the aerial parts of Elaeoselinum as-
clepium subsp. millefolium (Umbelliferae).4
Scheme 1
course of the reaction and the steric effects of that reagent
on our substrate.
The introduction of fluorine atoms in biologically active
substances can produce important modifications in their
activity and hence the interest in the development of new
stereospecific synthetic methods of fluorination.
In a recent article Lawrence et al.5 described the remote
acetamidation of (–) menthol with the electrophilic fluor-
inating reagent 1-chloromethyl-4-fluoro-1,4-diazoniabi-
cyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4 =
Selectfluorª).6This prompted us to use this reactive to in-
troduce a functional group in the B ring of kaurenoic acid
for which we transformed 1 into the 15a- and 15b-hy-
droxy derivatives 6, 7, 10 and 11 in order to study the
The starting diastereomeric hydroxykauranes were ob-
tained as shown in the Scheme 1. The methyl ester 2 of the
natural kaurenoic acid 1 was oxydized with selenium di-
oxide and tert-butyl hydroperoxide,7 affording the 15a-al-
cohol 3 (72%) together with the 17-aldehyde 4 (2%), and
the 15-ketone 5 (20%). Reduction of 3 with H2 at 1.3 atm
on 10% Pd/C in EtOH gave a mixture ca. 3:1 of the 16b-
and 16a-methyl derivatives 6 and 7 in 85% yield. The
conversion of these saturated 15a-alcohols into the re-
spective epimeric alcohols 10 and 11 was carried out in
59% and 63% yield respectively by a two-step sequence,8
i.e. oxidation with PDC and reduction of the ketones 8 and
Synlett 1999, No. 9, 1429–1431 ISSN 0936-5214 © Thieme Stuttgart · New York

1430
J. Anaya et al.
LETTER
9 with NaBH4. We also tried to obtain these 15b-alcohols favoured process. This last intermediate would react with
by NaBH4 reduction of the ketone 5 followed by catalytic a complex amine•HF (similar to comercial TREAT HF)13
hydrogenation of the alcohol 12, but only the 15b-hy- from the less hindered side (backwards to the leaving H-
droxy-16b-methyl isomer 10 was isolated in 35% yield.9
7a) to give the fluoroderivatives 13 and 14 respectively. A
process through a homolytic cleavage of the hypofluorite
A can be discarded because the intermediate oxygen rad-
ical is rather apart from H-7. Such intermediate oxygen
radical was generated by treatment of 6 with NIS under ir-
radiation with a tungsten lamp and the main reaction prod-
uct in this case was identified as the aldehyde 15, a
tricyclic abietane derivative which results from the cleav-
age of the C-8...C-15 bond as expected for a secondary ox-
ygen radical.
Once the starting diastereomeric alcohols were purified
we explored the remote functionalization of each one us-
ing the SelectfluorTM reagent (Scheme 2). The treatment
of 15a-hydroxy derivatives 6 or 7 with this reagent (2.2
mmol) in refluxing acetonitrile furnished a complex reac-
tion mixture from which the ketones 8 (30%) or 9 (38%)
and the 7b-fluoro derivatives 13 (10%) or 14 (12%) were
isolated by column chromatography on silica gel. On the
other hand, when the 15b-hydroxy isomers 10 or 11 were
treated under the same reaction conditions, the starting
material was recovered even after 16 h in refluxing aceto-
nitrile.10
+
N
F
N
+
CH2Cl
H
O
O
16
SelectfluorTM
F
7
+
H
H
H
2 HF
CH3CN
O
OH
F
H
H
B
A
CO2Me
CO2Me
6: 16β
7: 16α
13: 16β
14: 16α
+ 8
+ 9
H-F
Ð
+
R3N
H F
CHO
H-F
Reaction of 6 and 7 with SelectfluorTM
.
Scheme 2
13: 16β
14: 16α
15
H
CO2R
The structures of both 7b-fluorinated isomers 13 and 14
were rigorously established by 2D COSY, HMQC and
Possible reaction mechanism for the formation of 13 and 14.
1
HMBC NMR experiments. The H NMR signals of the
Scheme 3
3
geminal proton to the F atom in 13 (d= 4.68, dd, J7,6=4
and 2J7,F= 54 Hz) and 14 (d= 4.54, dd, 3J7,6= 4 and 2J7,F=54
Hz) let us assign the 7b-axial configuration for the fluor
atom and this was confirmed by the g-gauche shielding ef-
fects observed on the neighbouring carbon atoms C-5 and
C-9 while the C-14 signal remained unaffected.
The lack of reactivity in the case of the 15b-hydroxykau-
ranoates could be ascribed either to the difficulty of the re-
active in acceding from the b-face to form the
hypofluorite or to the difficulty in binding the hypofluo-
rite atom to the hydrogen atoms H-9 or H-11b along with
the steric hindrance for a backwards attack of the nucleo-
philic fluoride complex.
The N-fluoro quaternary salts such as SelectfluorTM are
strong oxidizing and fluorinating agents but their reaction
mechanism is not well understood and has been a subject
of debate. They can deliver positive fluoride ions repons-
able for the electrophilic fluorination reactions or compete
with the production of radical species that can give radical
coupling products.11
Further studies are in progress to increase the yields and
to try to understand the observed stereospecific fluorina-
tion with Selectfluor.TM
Although a reasonable radical process has been proposed
to explain the acetamidation of menthol with Select-
fluorTM in acetonitrile,5 we think that in our case the ob-
served fluorination should take place through a different
process and a tentative explanation could be as depicted in
Scheme 3. The first step may be the formation of an inter-
mediate hypofluorite, which can reply as a electrophilic
fluorinating reagent. In the case of the 15a-epimers 6 and
7 the F atom of the hypofluorite A can accede to the equa-
torial H-7a and progress by abstraction of this hydrogen
atom to form HF (captured by the amine) and oxidation at
C-15 to form the intermediate ketone B12 in an enthalpic
Acknowledgement
We thank the Junta de Castilla y León for the financial support (Pro-
ject SA22/97).
References and Notes
(1) Ghisalberti, E. L. Fitoterapia, 1997, LXIII, 303.
(2) a) Cross, B. E.; Stewart, J. C.; Stoddard, J. L. Phytochemistry
1970, 9, 1065. b) Becker, H.; Kempf, T. Z. Pflanzenphysiol.
1976, 80, 87.
(3) Villalobos, N.; Martín, L.; Mac’as, M. J.; Mancheño, B.;
Grande, M. Phytochemistry 1994, 37, 635.
Synlett 1999, No. 9, 1429–1431 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Fluorination of Kaurenoic Acid Derivatives by Remote Functionalization
1431
(4) Grande, M.; Morán, J. R.; Macías, M. J.; Mancheño, B.
Phytochem. Anal. 1993, 4, 19.
J = 7.6 Hz, Me-17), 0.88 (s, Me-20); 13C NMR (100 MHz,
CDCl3) d = 225.7 (C-15), 177.8 (C-19), 56.0 (C-5), 52.9 (C-
8), 51.2 (C-9), 50.8 (OMe), 46.6 (C-16), 43.7 (C-4), 39.9 (C-
10), 39.8 (C-1), 37.9 (C-14), 37.3 (C-13), 35.3 (C-7), 34.1 (C-
3), 30.2 (C-12), 28.7 (C-18), 20.4 (C-6), 18.3 (C-2), 18.2 (C-
11), 15.8 (C-17), 15.3 (C-20); MS (EI, 70 eV) m/z (%)= 332
(5) [M+], 289 (3) [M+–COMe], 274 (20) [M+–CO2Me], 121
(50), 107 (40), 91 (52), 79 (80), 55 (100). Fluoroketone 14: mp
206-209ûC; [a]D23= – 53 (c = 0.2, CHCl3); 1H NMR (400
MHz, CDCl3) d = 4.54 (dd, 3J7,6 = 4.0 Hz; 2J7,F = 54.0 Hz, H-
7), 3.65 (s, OMe), 1.17 (s, Me-18), 1.13 (d, J = 7.5 Hz, Me-
17), 0.92 (s, Me-20); 13C NMR (100 MHz, CDCl3) d = 221.4
(C-15), 177.8 (C-19), 92.7 (d, 1JC,F = 180 Hz, C-7), 53.5 (C-
8), 51.3 (OMe), 47.7 (C-5), 46.8 (C-9), 46.7 (C-16), 43.1 (C-
4), 39.6 (C-1), 39.4 (C-10), 37.6 (C-14), 37.1 (C-13), 33.2 (C-
3), 30.4 (C-12), 28.4 (C-18), 27.3 (C-6), 18.8 (C-2), 17.9 (C-
11), 15.9 (C-17), 15.4 (C-20); MS (EI, 70 eV) m/z (%) = 330
(4) [MH+–F], 290 (7) [MH+–CO2Me], 273 (3), 227 (10), 107
(50), 91 (54), 79 (53), 59 (52), 55 (100).
(5) Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Poppllewell,
A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629.
(6) a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif,
I.; Syvret, R. G. J. Chem. Soc., Chem. Commun.,1992, 595. b)
Banks, R. E.; Besheesh, M. K.; Mohialdin-Khaffaf, S. N.;
Sharif, I. J. Chem. Soc., Perkin Trans. 1 1996, 2069.
(7) S. C.; Dolan, J. MacMillan, J. Chem. Soc. Chem. Commun.
1985, 2741.
(8) Mancheño, B. Ph. D. Dissertation, University of Alicante,
Alicante, Spain, 1985.
(9) All compounds were fully characterised by 1H and 13C NMR,
IR and MS analyses. The relative configuration of the
diastereomers 6, 7, 10 and 11 was assigned according to the dC
of the following carbon atoms: C-9 (shielded in 10 and 11), C-
12 (shielded in 6 and 10), C-15 (shielded in 7 and 10), C-16
(shielded in 10), C-17 (deshielded in 11) and C-20 (shielded
in 10).
(10) General procedure for the reactions with SelectfluorTM: To a
solution of 7 (1.1 g, 3.3 mmol) in dry acetonitrile (50 mL) the
reactive (7.3 mmol) was added and the reaction mixture was
refluxed under argon atmosphere until dissapearence of the
starting material (6 h). The reaction product was purified by
column chromatography on silica gel with hexane/EtOAc
mixtures as eluent and pure ketones 9 (173 mg) and 14 (58
mg) were isolated. Ketone 9: mp 160-162°C; [a]D23= – 107
(c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d = 3.64 (s,
OMe), 2.29 (br d, J = 11.6 Hz, H-14), 1.16 (s, Me-18), 1.06 (d,
(11) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
1744.
(12) Banks, R. E.; Lawrence, N. J.; Poppllewell, A. L. Synlett 1994,
831.
(13) McClinton, M. A. Aldrichimica Acta 1995, 28, 31.
Article Identifier:
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Synlett 1999, No. 9, 1429–1431 ISSN 0936-5214 © Thieme Stuttgart · New York