Synthesis of deserpidine from reserpine

Article abstract of DOI:10.1021/np050179x

The Rauwolfia alkaloids reserpine (1) and deserpidine (2), two alkaloids from Rauwolfia species, have been widely used for their antihypertensive action. Deserpidine (2) is a compound with limited availability from natural sources, and its synthesis from 1 in six steps (41% overall yield) is reported here.

Full text of DOI:10.1021/np050179x

J. Nat. Prod. 2005, 68, 1629-1631
1629
Synthesis of Deserpidine from Reserpine
Greta Varchi,*,† Arturo Battaglia,† Cristian Samor`ı,† Eleonora Baldelli,† Bruno Danieli,‡ Gabriele Fontana,§
Andrea Guerrini,† and Ezio Bombardelli§
Istituto CNR per la Sintesi Organica e Fotoreattivita` “ISOF”, Area della Ricerca di Bologna, Via P., Gobetti 101,
40129 Bologna, Italy
Received May 25, 2005
The Rauwolfia alkaloids reserpine (1) and deserpidine (2), two alkaloids from Rauwolfia species, have
been widely used for their antihypertensive action. Deserpidine (2) is a compound with limited availability
from natural sources, and its synthesis from 1 in six steps (41% overall yield) is reported here.
Scheme 1. Synthesis of 11-OH Reserpic Acid Lactone (5)
Reserpine (1) is a naturally occurring alkaloid that has
been used for centuries in traditional Indian medicine. It
was first isolated in 19521 from Indian snake root,
Rauwolfia serpentina, and introduced for the treatment of
hypertension and schizophrenia later in the 1950s.2
Reserpine is known to act both centrally and peripherally
by depletion of biogenic amines such as noradrenaline,
dopamine, and serotonin. Its property of producing severe
depression as a side effect also made it useful in psychiatry
as a tranquilizer in the control of agitated psychotic
patients, even though it was replaced by more effective
drugs by the end of 1970s.3-5 In addition to its biological
properties, the complex molecular structure and the pres-
ence of numerous asymmetric centers stimulated the
development of several approaches toward its synthesis.6-9
The total synthesis of 1, developed by Woodward and co-
workers,6 is considered one of the historical landmarks in
natural product synthesis.
Deserpidine10,11 (2), isolated from the root of Rauwolfia
canescens, differs from reserpine (1) only by the absence
of a methoxy group at C-11. Deserpidine (2) shows an
interesting pharmacological profile and has been employed
for the treatment of hypertension and as a tranquilizer.
In addition, it appears to act as a controller of other cardiac
disorders.12
Results and Discussion
To the best of our knowledge, only one report has been
published on the transformation of reserpine (1) into
deserpidine (2) so far.15 The key step of Sakai’s procedure
is the cleavage of the yohimbane skeleton, which provides
a general method to give deserpidine derivatives having
different substituent groups on the indole part. Attempts
of direct removal of the methyl group at C-11 carried out
on reserpine (1)19 or on methyl reserpate (3)10 have failed,
affording only a complex mixture of byproducts or complete
demethylation including the methoxy group at C-17. Thus,
to favor demethylation at C-11 versus C-17, we first
synthesized the reserpic acid lactone (4) by reaction of
methyl reserpate (3)10 with aluminum isopropoxide (AIP).16
We assumed that the formation of the lactone ring could
have led to a skeletal rearrangement forcing the C-17
methoxy group to an axial position, thus no longer acces-
sible to demethylating agents. The reaction proceeded
smoothly, affording the desired product 4 in 91% isolated
yield. The same result was achieved by direct reaction of
reserpine (1) with AIP in refluxing xylene, affording
reserpic acid lactone (4) in 81% overall yield (Scheme 1).
Due to its poor availability from natural extracts,
deserpidine (2) has not been widely employed in medicine.
Reserpine usually occurs at about 0.10-0.16% of the
extract and deserpidine (2) at about 0.04%. Moreover, few
syntheses of deserpidine have been achieved so far;13,14 thus
we envisioned the possibility of developing a new and
efficient procedure for the synthesis of deserpidine (2) from
commercially available reserpine (1).
As we expected, the following treatment with BBr3 at 0 °C
9,17
in CH2Cl2
afforded only the C-11 demethylated adduct
5 in 92% yield.
Lactone 5 was converted to the sulfonyl ester derivative
6a (76% yield) by reaction with methanesulfonyl chloride
and triethylamine (Scheme 2). Subsequent hydrogenation
with molecular hydrogen performed in a Parr apparatus
at 50 psi and in the presence of Ni-Raney18 afforded
derivative 7 in 60% isolated yield, along with the free
alcohol 5 in 40% yield. To improve regioselectivity of the
reductive cleavage, we attempted to favor C-O bond fission
over S-O fission by replacement of the methanesulfonyl
group with a better leaving group, such as p-toluene-
* To whom correspondence should be addressed. Tel: +390516398283.
Fax: +390516398349. E-mail: G.Varchi@isof.cnr.it.
† ISOF-CNR, Bologna.
‡ Dipartimento di Chimica Organica ed Industriale, Milano.
§ Indena SpA, Milano.
10.1021/np050179x CCC: $30.25
© 2005 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/08/2005

1630 Journal of Natural Products, 2005, Vol. 68, No. 11
Varchi et al.
Scheme 2. Synthesis of Reserpic Acid Lactones (6a,b) and
Deserpidic Acid Lactone (7)
isopropoxide (0.75 g, 3.65 mmol) and 3 (0.20 g, 0.48 mmol) in
xylene (11 mL) was refluxed under vigorous stirring and under
nitrogen for 2 h. The product was separated by filtration and
washed with xylene (3 × 20 mL), then with ether (3 × 20 mL).
The residue was recrystallized from CHCl3, affording 0.17 g
(0.44 mmol, 91%) of 4 as a white solid.
Compound 4: [R]20D 16.6° (c 0.3, CHCl3); IR (KBr) νmax 3328,
2925, 1770, 1464, 1198 cm-1; 1H NMR (DMSO-d6, 400 MHz) δ
10.5 (1H, bs, NH), 7.18 (1H, d, J ) 8.4 Hz, H-9), 6.77 (1H, d,
J ) 2.3 Hz, H-12), 6.58 (1H, dd, J ) 8.4, 2.3 Hz, H-10), 4.75
(1H, t, J ) 4.0 Hz, H-18), 4.10 (1H, t, J ) 5.2 Hz, H-17), 3.73
(3H, s, OMe), 3.45 (1H, d, J ) 10.8 Hz, H-3), 3.35 (3H, s, OMe),
2.90 (1H, dd, J ) 12.0, 4.8 Hz), 2.76-2.64 (1H, m), 2.62-2.48
(5H, m), 2.42-2.25 (3H, m), 2.00 (1H, dd, J ) 14.4, 8.6 Hz,
H-19), 1.77-1.68 (1 H, m, H-14), 1.56 (1 H, dd, J ) 14.4, 4.0
Hz, H-19); 13C NMR (DMSO-d6, 100 MHz) δ 178.3, 155.7,
137.5, 135.2, 121.9, 118.6, 108.5, 106.7, 95.5, 77.7, 77.1, 58.8,
57.1, 55.9, 54.9, 53.2, 45.5, 35.4, 31.3, 27.7, 26.4, 22.2; anal. C
67.7%, H 7.17%, calcd for C22H26N2O4, C 69.09%, H 7.32%.
11-Hydroxy Reserpic Acid Lactone (5). Reserpic acid
lactone (4) (0.21 g, 0.55 mmol) was suspended in CH2Cl2 (8.0
mL) under argon, and the mixture was cooled to 0 °C. After
15 min, BBr3 was added (1.4 mL, 1.37 mmol, 1.0 M solution
in CH2Cl2) and the solution turned brick red. After 5 h the
reaction was quenched with 10 mL of an aqueous saturated
solution of NaHCO3 and extracted with 10 mL of CH2Cl2. The
aqueous phase was collected and extracted again with EtOAc
(3 × 15 mL). The eventual precipitate was filtered, dissolved
in a 1:1 THF/MeOH mixture, and added to the previously
obtained organic solution. The organic phases were combined
and dried. The solid residue was chromatographed (SiO2,
CH2Cl2/MeOH, 15:1, then 16:1) to give 5 as a white solid (0.19
Scheme 3. Synthesis of Deserpidine (2)
sulfonyl, thus favoring the formation of the desired product
7 instead of the free phenol 5 (Scheme 2). The reaction of
5 with p-toluenesulfonyl chloride and triethylamine af-
forded the desired sulfonyl ester 6b in 76% yield. Subse-
quent reductive cleavage as described afforded 7 in 85%
yield, thus confirming our initial hypothesis.
Deserpidic acid lactone (7) was then transformed into
methyl deserpidate (8) by means of sodium methoxide in
MeOH; the free alcohol 8 was than reacted at 5 °C with
3,4,5-trimethoxybenzoyl chloride in pyridine.10 The target
deserpidine (2) was isolated in 91% yield as a white solid
(Scheme 3).
g, 0. 51 mmol, 92%). Compound 5: [R]20 58.3° (c 0.3, THF);
D
MS (m/z) ESI: 369 (M + H)+; IR (KBr) νmax 3415, 3312, 2923,
1779, 1629 cm-1; 1H NMR (THF-d8, 400 MHz) δ 9.38 (1H, bs,
NH), 7.54 (1H, bs, OH), 7.07 (1H, d, J ) 8.4 Hz, H-9), 6.59
(1H, d, J ) 2.0 Hz, H-12), 6.44 (1H, dd, J ) 8.8, 2.0 Hz, H-10),
4.63 (1H, t, J ) 4.3 Hz, H-18), 4.03 (1H, t, J ) 5.2 Hz, H-17),
3.61 (1H, d, H-3, J ) 14.6 Hz,), 3.40 (3H, s, OMe), 2.98-2.82
(1H, m, H-5), 2.84-2.45 (7H, m, H-5, H-6, H-6, H-21, H-21,
H-15, H-16), 2.42-2.34 (1H, m, H-20), 2.22 (1H, dd, J ) 13.5,
2.0 Hz, H-14), 2.14-2.08 (1H, m, H-19), 1.90-1.82 (1H, m,
H-14), 1.61 (1H, dd, J ) 14.8, 3.9 Hz, H-19); 13C NMR (THF-
d8, 100 MHz) δ 176.6, 153.2, 138.0, 133.9, 121.3, 117.5, 108.4,
106.9, 96.6, 78.2, 76.7, 58.9, 56.2, 54.6, 53.1, 45.7, 35.8, 31.8,
27.9, 26.2, 22.1; anal. C 67.10%, H 7.46%, calcd for C21H24N2O4,
C 68.46%, H 7.60%.
Thus, an efficient six-step protocol for the conversion of
reserpine (1) to deserpidine (2) has been described. The key
step of the synthesis is the lactone ring formation, which
allows regioselective cleavage of the C-11 methoxyl group.
11-O-Methanesulfonyl Reserpic Acid Lactone (6a).
Et3N (0.01 mL, 0.11 mmol) was added to a solution of
11-hydroxy reserpic acid lactone (5) (0.03 g, 0.08 mmol) in 5.0
mL of dry THF, under N2. After stirring 10 min, methane-
sulfonyl chloride (0.01 mL, 0.09 mmol) was added and the
mixture was left at 20 °C for 60 h. Solvent was removed under
reduce pressure, and purification of the residue by flash
chromatography (SiO2, CH2Cl2/MeOH, 17:1) afforded 0.03 g
Experimental Section
General Experimental Procedures. Solvents were puri-
fied and dried prior to use. Reactions were monitored by thin-
layer chromatography on 0.25 mm E. Merck silica gel plates
(60 F254) using UV light as a visualizing agent or a 7%
(0.06 mmol, 76%) of 6a as a white solid. Compound 6a: [R]20
D
1
ethanolic phosphomolybdic acid as developing agent. H and
8.5° (c 0.3, CHCl3); IR (KBr) νmax 3295, 2923, 1758, 1179 cm-1
;
13C NMR spectra were recorded on a 400 MHz spectrometer
with Me4Si or CHCl3 (in CDCl3) as internal reference. Infrared
spectra were recorded on a Fourier transform IR spectrometer,
and values are reported in cm-1 units. Positive ion mass
spectra were obtained by direct infusion of 1.2 mM solutions
in 0.02 M ammonium acetate/MeOH, 20/80, using a Thermo-
quest LCQ-duo ion trap mass spectrometer (Finnigan) equipped
with an ESI ionization source. Methyl reserpate (3) and
deserpidine (2) from methyl deserpidate (8) were prepared as
reported elsewhere.10
ESIMS (m/z) 447 (M + H)+; 1H NMR (THF-d8, 400 MHz) δ
10.1 (1H, bs, NH), 7.35 (1H, d, J ) 8.8 Hz, H-9), 7.22 (1H, d,
J ) 2.0 Hz, H-12), 6.92 (1H, dd, J ) 8.8, 2.0 Hz, H-10), 4.65
(1H, t, J ) 4.4 Hz, H-18), 4.04 (1H, t, J ) 5.2 Hz, H-17), 3.67
(1H, d, J ) 11.6 Hz, H-3), 3.40 (3H, s, OMe), 3.06 (3H, s, OMe),
2.99-2.93 (1H, m, H-5), 2.89-2.81 (1H, m, H-6), 2.73 (1H, m,
H-21), 2.67-2.48 (5H, m, H-5, H-6, H-21, H-15, H-16), 2.44-
2.36 (1H, m, H-20), 2.27 (1H, dd, J ) 13.6, 1.6 Hz, H-14), 2.17-
2.09 (m, 1 H, H-19), 1.94-1.86 (1H, m, H-14), 1.62 (1H, dd, J
) 15.0, 4.0 Hz, H-19); 13C NMR (THF-d8, 100 MHz) δ 176.7,
145.0, 136.4, 127.6, 126.5, 117.8, 112.8, 107.6, 104.8, 78.2, 76.8,
58.8, 56.3, 54.5, 52.9, 45.7, 35.6, 31.7, 29.9, 27.9, 26.2, 21.9;
anal. C, 58.00%; H, 5.75%, calcd for C22H26N2O6S, C, 59.18%;
H, 5.87%.
Reserpic Acid Aactone (4). Procedure A: A mixture of
aluminum isopropoxide (10.5 g, 51.4 mmol) and reserpine (1)
(4.1 g, 6.74 mmol) in xylene (175 mL) was refluxed under
vigorous stirring for 6 h. Reserpic acid lactone (4), precipitated
from the solution, was filtered and washed with benzene (3 ×
40 mL) and ethyl ether (3 × 40 mL). The residue was
recrystallized from CHCl3, affording 2.07 g (5.46 mmol, 81%)
of 7 as a white solid. Procedure B: A mixture of aluminum
11-O-p-Toluenesulfonyl Reserpic Acid Lactone (6b).
Et3N (1.86 mL, 13.32 mmol) was added to a solution of 11-
hydroxy reserpic acid lactone (5) (0.70 g, 1.90 mmol) in 65 mL
of dry THF, under N2. After stirring 10 min p-toluenesulfonyl

Synthesis of Deserpidine from Reserpine
Journal of Natural Products, 2005, Vol. 68, No. 11 1631
chloride (1.09 g, 5.71 mmol) was added, and the mixture was
refluxed for 42 h. The crude mixture was than evaporated
under reduced pressure. Chromatography (SiO2, CH2Cl2/
MeOH, 17:1) afforded 0.75 g (1.44 mmol, 76%) of 6b as a white
7.80 (1H, bs, NH), 7.46 (1H, d, J ) 6.8 Hz), 7.31 (1H, d, J )
8.0 Hz), 7.14 (1H, td, J ) 6.8, 1.2 Hz), 7.09 (1H, td, J ) 7.6,
1.2 Hz), 4.46 (1H, bs, H-3), 3.79 (3H, s, OMe), 3.62-3.48 (5H,
m, OMe and 2H), 3.26-3.15 (2H, m), 3.06-2.91 (2H, m), 2.59-
2.45 (3H, m), 2.32-2.17 (2H, m), 2.03-1.91 (1H, m), 1.89-
1.71 (3H, m); 13C NMR (CDCl3, 100 MHz) δ 173.7, 135.7, 132.1,
127.8, 121.7, 119.7, 118.3, 111.1, 108.3, 81.6, 75.3, 61.2, 53.9,
52.1, 51.5, 51.3, 49.5, 34.7, 33.0, 32.4, 24.5, 16.9; anal. C
67.41%, H 7.20%, calcd for C22H28N2O4, C 68.73%, H 7.34%.
solid. Compound 6b: [R]20 -9° (c 0.3, CHCl3); IR (KBr) νmax
D
1
3282, 2927, 1756, 1177 cm-1; ESIMS (m/z) 523 (M + H)+; H
NMR (THF-d8, 400 MHz) δ 9.99 (1H, bs, NH), 7.64-7.62 (2H,
m, Ar), 7.32-7.30 (2H, m, Ar), 7.15 (1H, d, J ) 8.4 Hz, H-9),
6.90 (d, 1 H, J ) 2.0 Hz, H-12), 6.47 (1H, dd, J ) 8.4, 2.0 Hz,
H-10), 4.64 (1H, t, J ) 4.0 Hz, H-18), 4.03 (1H, t, J ) 5.2 Hz,
H-17), 3.62 (1H, d, J ) 12.0 Hz, H-3), 3.39 (3H, s, OMe), 2.93-
2.89 (1H, m, H-5), 2.84-2.43 (7H, m, H-5, H-6, H-6, H-21,
H-21, H-15, H-16), 2.38-2.32 (4H, m, Me, H-20), 2.22 (1H, dd,
J ) 13.6, 1.6 Hz), 2.10 (1H, m, H-19), 1.90-1.81 (1H, m, H-14),
1.60 (1H, dd, J ) 15.2, 4.0 Hz, H-19); 13C NMR (THF-d8, 100
MHz) δ 176.7, 144.9, 144.8, 136.2, 133.5, 129.6, 128.7, 126.3,
117.4, 113.2, 107.5, 105.0, 78.2, 76.7, 58.8, 56.3, 54.5, 52.9, 45.7,
35.7, 31.7, 29.9, 27.9, 26.2, 21.9, 20.8; anal. C 63.05%, H 5.70%,
calcd for C28H30N2O6S, C 64.35%, H 5.79%.
Deserpidine (2). A solution of 3,4,5-trimethoxybenzoyl
chloride (0.5 g, 2.17 mmol) in benzene (2.0 mL) was slowly
added to a solution of methyl deserpidate (8) (0.5 g, 1.30 mmol)
in dry pyridine (4.0 mL) at 5 °C. After disappearance of the
starting material, followed by TLC analysis of the reaction
mixture (5 days), the reaction was diluted with water (50.0
mL) and then treated with aqueous ammonia (10.0 mL). The
aqueous phases were extracted with CH2Cl2 (3 × 25 mL), dried
over sodium sulfate, filtered, and evaporated under reduced
pressure. The crude material was recrystallized from acetone,
yielding 0.17 g of 2 (0.44 mmol, 91%) as a white solid.
Compound 2: 1H NMR (CDCl3, 400 MHz) δ 7.83 (1 H, bs, NH),
7.48 (1 H, m), 7.33 (1 H, s), 7.33 (1 H, s), 7.32 (1 H, m), 7.17 (1
H, m), 7.12 (1 H, m), 5.07 (1 H, m), 4.52 (1 H, bs, H-3), 3.90 (1
H, dd, J1 ) 12.0 Hz, J2 ) 9.0 Hz), 3.89 (s, 3 H, OMe), 3.89 (3
H, s, OMe), 3.89 (3 H, s, OMe), 3.80 (3 H, s, OMe), 3.80 (3 H,
s, OMe), 3.20 (1 H, m), 3.20 (1 H, m), 3.04 (dd, 1 H, J1 ) 12.0
Hz, J2 ) 4.0 Hz), 2.98 (1 H, m), 2.70 (1 H, dd, J1 ) 12.0 Hz, J2
) 5.0 Hz), 2.54 (1 H, m), 2.47 (1 H, dd, J1 ) 12.0 Hz, J2 ) 2.0
Hz), 2.34 (1 H), 2.33 (1 H), 2.04 (1 H), 1.98 (1 H), 1.90 (1 H),
1.86 (1 H); 13C NMR (CDCl3, 100 MHz) δ 176.8, 169.4, 163.8,
161.0, 159.4, 144.0, 141.6, 141.6, 141.4, 140.1, 137.4, 133.1,
133.0, 115.5, 115.5, 86.2, 85.5, 82.3, 75.4, 74.0, 72.1, 67.8, 65.3,
61.8, 57.2, 50.7, 39.8, 27.3, 20.3.
Deserpidic Acid Lactone (7). Procedure A: Ni-Raney,
previously washed with H2O (twice), MeOH (twice), and EtOH
(once), was introduced (0.13 g, wet) into a Parr apparatus
under argon. Then 11-O-methanesulfonyl reserpic acid lactone
(6a) (0.02 g, 0.04 mmol), dissolved in 4.0 mL of anhydrous THF
and 6.0 mL of EtOH, was added. The hydrogenation was
carried out under a pressure of 50 psi. After 8 h the solution
was filtered through Celite and the Celite was carefully
washed with CHCl3 (6 × 10 mL) followed by MeOH (40 mL).
Solvent was removed under vacuum, and the residue was
purified by flash column chromatography (SiO2, CH2Cl2/
MeOH, 20:1), to afford 0.01 g of 7 as white solid (0.03 mmol,
60%), along with 0.005 g (0.01 mmol, 40%) of 5. Procedure B:
Ni-Raney, previously washed with H2O (twice), MeOH (twice),
and EtOH (once), was introduced (4.86 g, wet) into a Parr
apparatus under argon, followed by 11-O-p-toluenesulfonyl
reserpic acid lactone (6b) (0.30 g, 0.57 mmol) dissolved in 14
mL of anhydrous THF and 16.0 mL of EtOH. The hydrogena-
tion was carried out under 50 psi hydrogen pressure, and after
8 h the solution was filtered through Celite and carefully
washed with CHCl3 (6 × 40 mL) and MeOH (100.0 mL).
Solvent was removed under reduced pressure, and purification
of the residue by flash chromatography (SiO2, CH2Cl2/MeOH,
20:1) afforded 0.17 g of 7 as a white solid (0.49 mmol, 85%)
References and Notes
(1) Mu¨ller, J. M.; Schlittler, E.; Bein, H. J. Experientia 1952, 8, 338.
(2) Woodson, R. E.; Younken, H. W.; Schlitter, E.; Schneider, J. A.
Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology;
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(3) Wilkins, R. W.; Judson, W. E. New Eng. J. Med. 1953, 248, 48-56.
(4) Vakil, R. J. Br. Heart J. 1949, 11, 350-355.
(5) Bleuler, M.; Stoll, W. A. Ann. New York Acad. Sci. 1955, 61, 167-
173.
(6) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R.
W. J. Am. Chem. Soc. 1956, 78, 2023-2025.
along with 0.03 g (0.09 mmol, 15%) of 5. Compound 7: [R]20
D
7.9° (c 0.3, CHCl3); IR (KBr) νmax 3316, 2922, 1764, 1454 cm-1
;
(7) Pearlman, B. A. J. Am. Chem. Soc. 1979, 101, 6404-6408.
(8) Wender, P. A.; Schaus, J. M.; White, A. W. Heterocycles 1987, 25,
263-270.
ESIMS (m/z) 352 (M + H)+; 1H NMR (THF-d8, 400 MHz) δ
9.80 (1H, bs, NH), 7.32 (1H, d, J ) 7.6 Hz, H-9), 7.20 (1H, d,
J ) 7.6 Hz, H-12), 6.98-6.87 (2H, m, H-10, H-11), 4.65 (1H, t,
J ) 4.0 Hz, H-18), 4.04 (1H, t, J ) 5.2 Hz, H-17), 3.66 (1H, d,
J ) 11.6 Hz, H-3), 3.40 (3H, s, OMe), 2.97-2.92 (1H, m, H-5),
2.89-2.79 (1H, m), 2.78-2.33 (7H, m), 2.28 (1H, dd, J1 ) 13.7
Hz, J2 ) 2.0 Hz, H-14), 2.15-2.10 (m, 1 H, H-19), 1.94-1.85
(1H, m, H-14), 1.62 (1H, dd, J ) 14.8, 4.0 Hz, H-19); 13C NMR
(THF-d8, 100 MHz) δ 176.7, 136.9, 136.1, 127.6, 120.2, 118.3,
117.4, 110.5, 107.2, 78.2, 76.7, 58.9, 56.2, 54.6, 53.1, 45.7, 35.8,
31.7, 27.9, 26.2, 22.1; anal. C 70.10%, H 6.74%, calcd for
(9) Ryohal, J.; Hiroshi, H.; Shiro, K. Polym. Bull. 1997, 38, 273-275.
(10) MacPhillamy, H. B.; Huebner, C. F.; Schlittler, E.; St. Andre´, A. F.;
Ulshafer, P. R. J. Am. Chem. Soc. 1955, 77, 4335-4343.
(11) Lounasmaa, M.; Tolvanen, A. Heterocycles 1985, 23, 371-375.
(12) Fabricant, D. S.; Farnsworth, N. R. Environmental Health Perspec-
tives 2001, 109, 69-75.
(13) Naito, T.; Hirata, Y.; Miyata, O.; Ninomiya, I.; Inoue, M.; et al. Chem.
Pharm. Bull. 1989, 37, 901-906.
(14) Mariano, P. S.; Baxter, E. W.; Labaree, D.; Ammon, H. L. J. Am.
Chem. Soc. 1990, 112, 7682-7692.
(15) Sakai, S.; Ogawa, M. Heterocycles 1978, 10, 67-71.
(16) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R.
W. Tetrahedron 1958, 2, 1-57.
C
213H24N2O3, C 71.57%, H 6.86%.
Methyl Deserpidate (8). Deserpidic acid lactone (7) (0.14
(17) Rice, K. C. J. Med. Chem. 1977, 20, 164-165.
(18) Kenner, G. W.; Murray, M. A. J. Chem. Soc. 1949, V, S178-S181.
(19) We attempted removal of the C-11 methyl group applying classical
procedures normally employed for phenolic ethers deprotection. For
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Sharghi, H.; Tamaddon, F. Tetrahedron 1996, 52, 13623-13640. (c)
Daley, L.; Maresse, P.; Bertounesque, E.; Monneret, C. A. Tetrahedron
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g, 0.40 mmol) was dissolved in 27 mL of anhydrous MeOH
under N2 atmosphere. NaOMe (0.03 g, 0.60 mmol) was added
to the reaction mixture, which was then refluxed for 90 min.
The reaction was quenched by addition of 0.2 mL of acetic acid,
and the crude mixture was evaporated under reduced pressure,
washed with a 0.2 M solution of NaOH, and extracted with
CHCl3 (4 × 25 mL). The organic phases were dried, filtered,
and evaporated under reduced pressure. Flash chromatogra-
phy purification of the crude compound (SiO2, CH2Cl2/MeOH,
10:1) afforded 0.17 g (0.38 mmol, 95%) of 8 as a white solid.
Compound 8: [R]20D -80° (c 0.2, pyridine); IR (KBr) νmax 3454,
3374, 2925, 1722, 1463 cm-1
;
1H NMR (CDCl3, 400 MHz) δ
NP050179X