Synthesis of betulin derivatives with solid supported reagents

Article abstract of DOI:10.1081/SCC-100104070

Betulin-allobetulin transformation is effected with ferric nitrate or ferric chloride adsorbed onto silica gel or alumina, in excellent yields. In addition, allobetulin can be converted to allobetulone with silica adsorbed ferric nitrate or to 19β,28-epoxy-A-neo- 18α-olean-3(5)-ene and 19β,28-epoxy-A-neo-5β-methyl-25-nor-18α-olean-9-ene with silica or alumina adsorbed ferric chloride.

Full text of DOI:10.1081/SCC-100104070

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SYNTHESIS OF BETULIN
DERIVATIVES WITH SOLID
SUPPORTED REAGENTS
a
b
Serge Lavoie , André Pichette , François-Xavier
a
c
d
Garneau , Michel Girard & Daniel Gaudet
a
Université du Québec à Chicoutimi, LASEVE, 555
boul. Université, Chicoutimi, Queébec, G7H 2B1,
Canada
b
Université du Québec à Chicoutimi, LASEVE, 555
boul. Université, Chicoutimi, Queébec, G7H 2B1,
Canada
c
Sir F. G. Banting Research Center, Bureau of
Biologics and Radiopharmaceuticals, Therapeutic
Products Program, Health Canada, Tunney's
Pasture, Ottawa, Ontario, K1A 0L2, Canada
d
Chicoutimi Hospital Research Unit, 305 St-
Vallier, Chicoutimi, Québec, G7H 5H6, Canada
Version of record first published: 02 Aug 2010
To cite this article: Serge Lavoie, André Pichette, François-Xavier Garneau, Michel
Girard & Daniel Gaudet (2001): SYNTHESIS OF BETULIN DERIVATIVES WITH SOLID
SUPPORTED REAGENTS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:10, 1565-1571
To link to this article: http://dx.doi.org/10.1081/SCC-100104070

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SYNTHETIC COMMUNICATIONS, 31(10), 1565–1571 (2001)
SYNTHESIS OF BETULIN DERIVATIVES
WITH SOLID SUPPORTED REAGENTS
1
Serge Lavoie, Andre
Franc¸
,2
Pichette,1,2,*
ois-Xavier Garneau, Michel Girard,
´
1
3
2
and Daniel Gaudet
1
LASEVE, Universite
Universite, Chicoutimi, Que
Chicoutimi Hospital Research Unit, 305 St-Vallier,
Chicoutimi, Quebec, Canada, G7H 5H6
Bureau of Biologics and Radiopharmaceuticals,
Therapeutic Products Program, Health Canada,
´
du Que
´
bec a
´
`
Chicoutimi, 555 boul.
bec, Canada, G7H 2B1
´
2
´
3
Sir F. G. Banting Research Center, Tunney’s Pasture,
Ottawa, Ontario, Canada, K1A 0L2
ABSTRACT
Betulin–allobetulin transformation is effected with ferric
nitrate or ferric chloride adsorbed onto silica gel or alumina,
in excellent yields. In addition, allobetulin can be converted to
allobetulone with silica adsorbed ferric nitrate or to 19b,28-
epoxy-A-neo-18a-olean-3(5)-ene and 19b,28-epoxy-A-neo-5b-
methyl-25-nor-18a-olean-9-ene with silica or alumina adsorbed
ferric chloride.
*
Corresponding author.
1
565
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
566
LAVOIE ET AL.
Betulin (1), a triterpene of the lupane family, is found in large amounts
1
in white birch bark (Betula paperyfera March). Since it is abundant and
easy to extract and purify, betulin is an interesting substrate for synthesizing
2
–4
several triterpene derivatives presenting various biological activities.
Allobetulin, one of these derivatives, is often prepared from betulin in low
5
–10
yields, using various acids.
good yields, with acid reagents previously adsorbed onto solid supports or
This transformation was recently achieved in
1
1
even with certain solid supports used alone.
Our laboratory is interested in developing simple methods for synthe-
sizing derivatives of betulin. Various oxidizing agents adsorbed onto solid
supports have been tested, since, in some cases, selective oxidations can
1
2
be performed with these reagents under mild reaction conditions. It
has been reported that alcohol functions can be efficiently oxidized with
1
iron nitrate (Fe(NO ) ) adsorbed onto clays or silica gel. However, in
3
3
3
the course of our studies on the oxidation of betulin, we discovered that
allobetulin (2) could be quantitatively prepared with this reagent, and
in very short reaction times (Scheme 1). In addition, we noted that allobe-
tulone could be synthesized in good yields when longer reaction times
were used.
The reagent was prepared by grinding iron nitrate with silica gel or
alumina. The obtained yellowish powder was combined with betulin (1)
Scheme 1.
dissolved in CH Cl and then refluxed. Under these conditions, allobetulin
2
2
(
2) was obtained in yields exceeding 95% in 15 min (Table 1). If the reaction
is maintained for 6 h, allobetulin (2) is transformed into allobetulone (3)
in 70% yield. To our knowledge, the synthesis of allobetulone (3) from
betulin (1) in a single step has never been reported. Other allobetulone
(
synthetic steps.
3) synthetic approaches reported in the literature always involve two
1
4,15
The transformation shown in Scheme 1 occurs via a rearrangement
of betulin’s E ring (1). This rearrangement is due to the Lewis acid

BETULIN DERIVATIVES
1567
a
Table 1. Transformation of Betulin with Solid-Supported Reagents
b
Yield (%)
Solid
support
Reaction
time
Reaction
Reagent
2
3
4
5
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeCl3
FeCl
FeCl
FeCl3
Fe(NO
Fe(NO
Fe(NO
3
3
SiO
SiO
2
2
5 m
2 h
5 m
2 h
5 m
2 h
15 m
6 h
>95
—
>95
—
>95
—
>95
—
—
—
—
—
—
—
—
70
—
—
—
55
—
55
—
55
—
trace
—
—
—
45
—
45
—
45
—
trace
—
—
Al O
2
3
3
3
3
Al
—
—
2
O
3
3
3
)
3
)
3
)
3
SiO
SiO
2
2
Al
—
2
O
3
30 m
90 m
>95
>95
1
0
Fe(NO3)3
a
3 2 2
FeX /adsorbent ratio 1:4 (wt/wt), solvent: CH Cl , room temperature, magnetic
b
stirring; GC-determined. Isolated yields are available in Experimental.
nature of the iron of Fe(NO ) , and is not due to the adsorbent.
3
3
Indeed, when betulin is combined with the adsorbent alone, no reaction
is observed. However, the reaction between the unadsorbed Fe(NO3)3
and betulin is much slower, indicating that the adsorbent greatly
accelerates the reaction’s progression. The transformation to allo-
betulin (2) with a well-known Lewis acid such as FeCl3 adsorbed
onto either of the two adsorbents is even faster than with the adsorbed
Fe(NO ) (Table 1). These observations seem to indicate that Fe(NO )
3 3
3
3
initially acts as a Lewis acid rather than an oxidant.
Allobetulone (3) can be obtained in excellent yields if the reaction
between Fe(NO ) adsorbed on silica gel and betulin is maintained for a
3
3
6
-h period. In this case, Fe(NO ) adsorbed onto silica gel first transforms
3 3
betulin into allobetulin and subsequently acts as an oxidant by transforming
the secondary alcohol function into a ketone. It is important to specify that
oxidation of the secondary alcohol is solely observed when silica gel is used
as the adsorbent. Increasing the reaction time between betulin and FeCl or
3
adsorbed FeCl results in the formation of two allobetulin-derived products:
3
1
9b,28-epoxy-A-neo-18a-olean-3(5)-ene (4) and 19b,28-epoxy-A-neo-5b-
methyl-25-nor-18a-olean-9-ene (5) (Scheme 2). The formation of such
ring-A contracted products has been previously studied in lupane-type tri-
1
6
terpenes and rationalized on the basis of Wagner-Meerwein rearrange-
ments. As such, the products resulted from 1,2-hydride and alkyl shifts
following the initial generation of a carbocation by the acid-catalyzed loss
of the 3b-OH in ring A.

1
568
LAVOIE ET AL.
Scheme 2.
EXPERIMENTAL
General
Reagents and solid supports were bought and used without purifica-
tion. GC-MS analyses were performed with a HP 5890/HP 5972 instrument.
Seperation was achieved on a 25 m ꢀ 0.25 mm i.d. HP-5MS capillary column.
ꢁ
ꢁ
The operating conditions were as follows: injector temperature 280 C,
column temperature 100 C (1 m), 100 –280 C (25 C/m), 280 –325 C
(
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ ꢁ
5 C/m) and 325 C (30 m), carrier gas (helium) flow-rate 1 mL/m. NMR
spectra were done with Bruker (300 and 400 MHz) instruments. Thin-
layer chromatographies were performed on silica gel-covered glass plates
6
0F254 (Merck).
Isolation of betulin (1)
Finely ground birch bark (100 g) was macerated under reflux in 1 L of
chloroform. The mixture was filtered and then vacuum-evaporated to obtain
2
8 g of crude betulin (1). This extract was purified by silica gel chromato-
graphy using a petroleum ether and ethyl acetate solution as eluent (90:10 to
5:15). Betulin (17 g) was obtained as a white solid, which was >95% pure
8
by GC and showed only one spot on TLC. Only signals due to this
compound were observed and were essentially identical to the NMR
1
7 1
spectrum of the literature.
H NMR (300 MHz, CDCl ) d 4.68 (1 H, d,
3
H-29), 4.58 (1 H, d, H-29), 3.77 (1 H, d. J ¼ 7.8 Hz, H-28), 3.31 (1 H, d,
J ¼ 7.8 Hz, H-28), 3.18 (1 H, m, H-3), 2.38 (1 H, m, H-19), 1.02–1.95
(
6
6
complex, CH , CH), 1.68, 1.02, 0.98, 0.96, 0.82, 0.76 (18 H, all s,
2
þ
ꢀ CH ); EIMS, m/z, 442 (M , 5%), 43 (100), 95 (96), 55 (96), 81 (95),
3
9 (84), 41 (81), 67 (79), 93 (79), 189 (76).

BETULIN DERIVATIVES
1569
Example of Reagent Preparation
Fe(NO ) ꢂ 9H O (0.2 g, 0.50 mmol) and silica gel (0.8 g) were ground
3
3
2
in a mortar until a fine homogeneous powder was obtained. Other reagents
were prepared using the same mass ratio (1:4).
Preparation of allobetulin (2)
Betulin (1, 50 mg, 0.11 mmol) was dissolved into 10 mL of freshly
distilled dichloromethane. The solution was heated at reflux, then 456 mg
of Fe(NO ) /SiO (0.22 mmol Fe(NO ) ) was added and the resulting mix-
3
3
2
3 3
ture was stirred for 30 m. When the reaction was over (followed by TLC,
approximately 30 m), the solution was filtered through a sintered glass
funnel covered with silica gel. The solution was then thoroughly rinsed
with a solution of 2% methanol in dichloromethane. The solvent was
removed by vacuum distillation and 45.5 mg of allobetulin (2) was obtained
as an amorphous solid in 91% yield. The isolated product was >95% pure
by GC and showed only one spot by TLC. Only signals due to this
compound were observed and essentially identical to the NMR spectrum
1
5 1
of the literature. H NMR (300 MHz, CDCl ) d 3.76 (1 H, d, J ¼ 7.8 Hz,
3
H-28), 3.53 (1 H, s, H-19), 3.44 (1 H, d, J ¼ 7.8 Hz, H-28), 3.20 (1 H, m, H-3),
1
7
.01–1.78 (complex, CH , CH), 0.98, 0.93, 0.92, 0.85, 0.80, 0.77 (21 H, all s,
2
þ
ꢀ CH ); EIMS, m/z, 442 (M , 9%), 81 (100), 95 (92), 69 (90), 43 (86), 189
3
(
80), 55 (78), 207 (70), 41 (69), 135 (59).
The reagent can also be prepared with FeCl ꢂ6H O and alumina as
3
2
solid support.
Preparation of allobetulone (3)
To obtain allobetulone (3), the previous reaction was maintained
another 6 h. Afterward, the mixture was filtered with a sintered glass
funnel covered with silica gel (1 cm). Thorough rinsing with a dichloro-
methane solution containing 2% methanol was required for maximum
product recovery. The solvent was vacuum evaporated and allobetulone
(3) was recovered as an amorphous solid (35 mg, 70%) by silica gel
chromatography with a petroleum ether/ethyl acetate 95:5 mixture. The
isolated product was >95% pure by GC and showed only one spot on
TLC. Only signals due to this compound were observed and were essentially
1
5 1
identical to the NMR spectrum of the literature.
H NMR (300 MHz,
CDCl ) d 3.78 (1 H, d, J ¼ 6 Hz, H-28), 3.53 (1 H, s, H-19), 3.45 (1 H, d,
3

1
570
LAVOIE ET AL.
J ¼ 6 Hz, H-28), 2.46 (2 H, m, H-2), 1.94 (1 H, m, H-5), 1.20–1.75 (complex,
CH , CH), 1.08, 1.03, 1.01, 0.94, 0.93, 0.92, 0.80 (21 H, all s, 7 ꢀ CH );
2
3
þ
EIMS, m/z, 440 (M , 22%), 81 (100), 55 (91), 69 (85), 95 (79), 41 (75), 43
(
66), 67 (63), 93 (54), 107 (54).
Preparation of 19b,28-epoxy-A-neo-18a-olean-3(5)-ene (4) and of
1
9b,28-epoxy-A-neo-5b-methyl-25-nor-18a-olean-9-ene (5)
These products were obtained by maintaining the reaction with ferric
chloride an additional hour. The reaction medium was then filtered with a
sintered glass funnel covered with a layer of silica gel (1 cm). Both products
were isolated by chromatography with 10% AgNO -SiO using a
3
2
petroleum ether solution containing dichloromethane as eluent (90:10 to
5
0:50 v/v). 19b,28-Epoxy-A-neo-18a-olean-3(5)-ene (4, 10 mg) and 19b,28-
epoxy-A-neo-5b-methyl-25-nor-18a-olean-9-ene (5, 15 mg) were obtained
as amorphous solids, which where >90% pure GC and showed only one
spot by TLC. Only signals due to these compounds were observed and were
1
1
1
essentially identical to the NMR spectra of the literature. 4 H NMR
(
(
CDCl ) d 3.81 (d, J ¼ 8 Hz, 1 H, H-28), 3.57 (s, 1 H, H-19), 3.47
3
d, J ¼ 8 Hz, 1 H, H-28), 2.66 (m, 1 H, H-4), 1.10–2.31 (complex, CH ,
2
CH), 1.00, 0.94 (all d, J ¼ 6.9 Hz, 6 H, H-23 and H-24), 1.06, 0.96, 0.89,
þ
0
.88, 0.82 (all s, 21 H, 5ꢀCH ); EIMS, m/z, 424 (M , 5%), 121 (100), 381
3
1
82), 135 (79), 93 (72), 136 (67), 107 (65), 161 (59), 81 (59), 95 (54). 5 H NMR
(
(
CDCl ) d 3.82 (d, J ¼ 8 Hz, 1 H, H-28), 3.57 (s, 1 H, H-19), 3.47 (d, J ¼ 8 Hz,
3
1
H, H-28), 1.10–2.31 (complex, CH , CH), 0.95, 0.91 (all d, J ¼ 6.6 Hz, 6 H,
2
H-23 et H-24), 1.08, 0.95, 0.82, 0.80, 0.79 (all s, 21 H, 5 ꢀ CH ); EIMS, m/z,
3
þ
4
(
24 (M , 28%), 55 (100), 69 (89), 119 (79), 105 (78), 41 (72), 95 (70), 189
69), 81 (67), 91 (64).
ACKNOWLEDGMENTS
We thank Jimmy Bouchard, Bruce Black, and Brian Dawson for their
assistance in the NMR experiments. The financial support of the Fondation
de l’UQAC is gratefully acknowledged. SL thanks PAIR, Bourse
´
Paul-Emile-Boulet, and Association des diplo
ˆ me(e)s et ami(e)s de I’UQAC
´
for graduate scholarships.

BETULIN DERIVATIVES
1571
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Received in the USA August 3, 2000