RETRACTED ARTICLE: First stereoselective total synthesis of (-)-(2R,10S)-megapodiol

Article abstract of DOI:10.1016/j.tetasy.2005.01.011

The first and efficient total synthesis of (-)-(2R,10S)-megapodiol 2 was accomplished stereoselectively, using a Sharpless asymmetric epoxidation of a trans allylic alcohol, intramolecular epoxide opening by phenolic hydroxyl, and cyclization as the key r

Full text of DOI:10.1016/j.tetasy.2005.01.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 917–919
First stereoselective total synthesis of (ꢀ)-(2R,10S)-megapodiol
Ramadas Sathunuru* and Jean-Charles Quirion
Laboratoire d’ Heterochimie Organique associe’ au CNRS, IRCOF, INSA et Universite’ de Rouen,
Rue Tesniere 76821 Mont Saint—Aignan cedex, France
Received 22 November 2004; accepted 11 January 2005
Abstract—The first and efficient total synthesis of (ꢀ)-(2R,10S)-megapodiol 2 was accomplished stereoselectively, using a Sharpless
asymmetric epoxidation of a trans allylic alcohol, intramolecular epoxide opening by phenolic hydroxyl, and cyclization as the key
reaction steps.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(ꢀ)-(2R)-Megapodiol1 1 is a 2,3-dihydrobenzofuran iso-
lated from the ground plant Baccharis megapotamica, a
Brazilian shrub of the genus Baccharis that belongs to
the family of Asteraceae. Compound 1 showed high
activity in vivo against P388 leukemia in mice and high
cytotoxicity in vitro against KB cells.2 The structure of
1 has not been reported earlier and the absolute stereo-
chemistry at C-10 was also not known. However the
configuration at C-2 was found to be R by degradation
studies.3 Due to its interesting antileukemic activity and
our interest in the chemistry of chiral 2,3-
dihydrobenzofuran antifungals,4 we were attracted to-
ward its total synthesis. Herein we report the first and
efficient total synthesis of (ꢀ)-(2R,10S)-megapodiol
2, thereby establishing its absolute stereochemistry
(Fig. 1).
The retrosynthesis envisaged for the synthesis of (ꢀ)-
(2R,10S)-megapodiol 2 is shown in Scheme 1. The key
step involved in this sequence was the intramolecular
epoxide opening by phenolic hydroxyl4 with simulta-
neous cyclization affording the 2,3-dihydrobenzofuran
moiety. The epoxide 3 was prepared by Sharpless asym-
metric epoxidation5 of trans-allylic alcohol6 4, which
was in turn prepared from 1-methyl-1-vinyloxirane7 6
and p-hydroxyacetophenone 7 in a six-step sequence
involving regiospecific addition8 through a p-allylpalla-
dium complex, acetylation, Claisen rearrangement,8
protection, reduction, and deprotection strategy
(Scheme 1).
Accordingly, the known6 trans allylic alcohol 4 was pre-
pared from p-hydroxyacetophenone, by regiospecific
opening8 by the phenolic hydroxy group of p-hydroxy-
acetophenone to 1-methyl-1-vinyloxirane7 6 through a
p-allylpalladium complex intermediate obtained from
vinyloxirane and Pd(0). The crude reaction product 5
(95%) was then reacted with Ac2O to protect the alco-
holic hydroxyl as an acetoxy group and this gave 8
(98%). By using dry HCl, the latter was transformed8
(Claisen rearrangement) into 9 (98%). Alkylation of 9
with BnBr/K2CO3 in acetone afforded 10 (92%). NaBH4
reduction of the keto compound 10 in methanol gave
alcohol 11 (90%). Reaction of 11 with TBDMSCl and
imidazole, furnished 12 (90%). Further, deprotection
of the acetyl group from 12 with K2CO3, MeOH, and
H2O afforded trans allylic alcohol 4 (97%). The structure
of 4 was unambiguously assigned based on the spectral
and NOE studies (Fig. 2). Introduction of chirality on
OH
H
OH
OH
CH3
O
OH
H
O
CH3
H3C
H3C
O
(-)-(2R,10S)-2
Megapodiol
O
(-)-(2R)-1
Megapodiol
Figure 1.
*
Corresponding author at present address: Department of Chemistry,
Southern Methodist University, Fondern Science Bldg, 3215 Daniel
Avenue, Dallas, TX 75275, USA. Tel.: +1 214 768 2735; fax: +1 214
768 4089; e-mail: rsathunu@mail.smu.edu
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.011

918
R. Sathunuru, J.-C. Quirion / Tetrahedron: Asymmetry 16 (2005) 917–919
OR
1
OR
1
OH
CH
O
H
O
OH
OH
3
O
H C
3
H C
3
3
OH
CH
H C
3
OR
CH
OR
3
2
R = TBDMS, R = Bn
1
R = TBDMS, R = Bn
1
O
4
3
OH
CH
3
O
H C
3
H C
3
+
H C
3
OH
O
7
6
O
5
Scheme 1. Retrosynthetic analysis.
R
H
H
H
H
OH
the trans-allylic double bond through Sharpless asym-
metric epoxidation (SAE)5 using L-(+)-DET as the
chiral reagent afforded 3 (86%) with a (ꢀ)-(2R,3S)-con-
figuration and 95% de (determined by NMR analysis).
Debenzylation of 3 with H2, Pd/C in MeOH, followed
by cyclization with K2CO3, NEt3 afforded 2,3-
dihydrobenzofuran 14 (70%) rather than the isomeric
3-hydroxychroman.4 (ꢀ)-(2R,10S)-Diol 14 on acetyl-
ation with Ac2O, DMAP (cat) and Et3N in CH2Cl2 gave
H C
3
CH
3
H
R
1
R=OBn, R1=OTBDMS
4
Figure 2. NOE studies on 4.
CH3
OR
O
OH
O
H3C
OAc
e
CH3
H3C
a,b
f,g
c,d
OR
+
H3C
H3C
5 R = H (95%)
O
O
9 R = H (98%)
O
8 R = Ac (98%)
7
10 R = Bn (92%)
6
OBn
OBn
OBn
O
OR1
H3C
OH
H3C
OAc
CH3
i ,
j
H3C
h
CH3
OR
CH3
OTBDMS
OH
11 ( 90% )
12 R = TBDMS; R1 = Ac (90%)
4 R = TBDMS; R1 = H (97%)
(-)-(2S,3S)
3 ( 86% )
OR
OR
H
OH
H
..
..
O
H
O
O
OH
CH3
O
H3C
CH3
k,l
OH
H3C
H3C
_
(
) -(2R,10S)
OR1
CH3
OTBDMS
(-)-(2R,10S)
14 ( 70% )
OTBDMS
15 R = Ac; R1 = TBDMS (90%)
16 R = Ac; R1 = H (70%)
(-)-(2S,3S)
13
HE
HD
Hc
OH
OH
O
OAc
OAc
CH3
H
O
CH3
n
H3C
HB
H3C
HA
m
O
O
(-)-(2R,10S)
17 ( 75% )
(-)-(2R,10S)
2 ( 80%)
Scheme 2. Reagents and conditions : (a) Pd(PPh3)4, CH2Cl2, rt, 4 h; (b) Ac2O, Et3N, DMAP, AcOEt, rt, 4 h; (c) HCl(g), CH2Cl2, rt, 2 min; (d) BnBr,
K2CO3, acetone, reflux, 12 h; (e) NaBH4, MeOH, 0 ꢁC, 2 h; (f) TBDMS–Cl, imidazole, DMAP (cat), CH2Cl2, 0 ꢁC 15 min then rt, 10 h; (g) K2CO3,
MeOH, H2O, rt, 2 h; (h) t-BuOOH, Ti(O-i-Pr)4, L-(+)-DET, CH2Cl2, ꢀ24 ꢁC, 20 h; (i) H2, Pd/C, MeOH, rt, 4 h; (j) K2CO3, NEt3, rt, 4 h; (k) Ac2O,
DMAP (cat), NEt3, CH2Cl2, 0 ꢁC, 15 min then rt, 5 h; (l) Bu4NF, AcOH, THF, rt, 24 h; (m) PCC, NaOAc, Celite, CH2Cl2, 0 ꢁC 15 min then rt, 6 h;
(n) K2CO3, MeOH, H2O, rt, 1 h.

R. Sathunuru, J.-C. Quirion / Tetrahedron: Asymmetry 16 (2005) 917–919
919
5. (a) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic: New York, 1985; Vol. 5,
p 247; (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc.
1980, 102, 5974; (c) Gao, Y.; Hanson, R. M.; Klunder, J.
M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765; (d) Rossiter, B. E. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
New York, 1985; Vol. 5, p 193; (e) Pfenniger, A. Synthesis
1986, 89.
6. Goujon, J. Y.; Duval, A.; Kirschleger, B. J. Chem. Soc.,
Perkin Trans. 1 2002, 496.
7. Coulonge, J.; Descotes, G.; Bahurd, Y. Bull. Soc. Chim.
Fr. 1965, 3, 619.
(ꢀ)-(2R,10S)-15 (90%). Deprotection of the (ꢀ)-
(2R,10S)-TBDMS group of 15 with Bu4NF and AcOH
in THF afforded (ꢀ)-(2R,10S)-alcohol 16 (70%). PCC
oxidation of (ꢀ)-(2R,10S)-16 in CH2Cl2 and NaOAc
furnished (ꢀ)-(2R,10S)-17 (75%). Removal of the
OAc protecting groups 17 with K2CO3, MeOH, and
25
D
H2O afforded (ꢀ)-(2R,10S)-2 (80%) (Scheme 2), ½aꢁ
¼
25
D
ꢀ64:1 (c 1.25, MeOH) [lit.1 ½aꢁ ¼ ꢀ52:0 (c 1.00,
MeOH)] with >99.0% ee (determined by chiral HPLC
analyses),9 the spectroscopic data10 of which were iden-
tical with those of the natural product.
8. Marquard, I. Eur. Patent Appl. EP183, 042 (Hoffman, F.;
La Roche; Co, A.-G.) Chem. Abstr. 1986, 105,
172047y.
3. Conclusion
9. The enantiomeric excess (ee) of (ꢀ)-(2R,10S)-14, -15, -16,
-17, and -2 were determined by chiral HPLC analyses
using a Chiracel OD column and Chiracel OJ col-
umn (25 · 0.46 cm, Daicel, Japan) eluent: hexane–i-
PrOH).
In summary we have demonstrated for the first time the
total synthesis of megapodiol in a highly stereoselective
manner using Sharpless asymmetric epoxidation as key
step. Our method involves simple and readily available
reagents, which makes it useful synthetic route for the
total synthesis of megapodiol.
10. Spectroscopic data: data for compound 2: 1H NMR
(200 MHz, CDCl3): d 1.21 (3H, s, CH3-12), 2.49 (s, 3H,
CH3-14), 3.19 (1H, dd, J = 16.0, 8.0 Hz, CH2-3, HA), 3.27
(1H, dd, J = 16.0, 10.0 Hz, CH2-3, HB), 3.48 (1H, d,
J = 16.0 Hz, CH2OH-11, HD), 3.70 (1H, d, J = 16.0 Hz,
CH2OH-11, HE), 4.85 (1H, m, H-2, HC) 6.73 (1H, d,
J = 10.0 Hz, H-8), 7.68 (1H, dd, J = 10.0, 2.0 Hz, H-7),
7.75 (1H, br s, H-5); 13C NMR (50.3 MHz, CDCl3): 19.9
(CH3-12), 26.7 (CH3-14), 29.9 (C-3), 68.4 (CH2OH-11),
73.1 (C-10), 89.2 (C-2), 109.5 (C-8), 125.6 (C-5), 127.8 (C-
6), 130.3 (C-7), 131.6 (C-4), 163.7 (C-9), 197.8 (C@O).
Anal. Calcd for C13H16O4 (236.10): C, 66.09; H, 6.83.
Found: C, 66.18; H, 6.94. MS: m/z (relative intensity) 236
(M+, 18), 204 (6), 187 (9), 162 (35), 147 (19), 119 (25), 91
(25), 75 (12), 57 (20), and 43 (100). FABHRMS: Calcd
C13H16O4 (M+) 236.105248. Found: 236.105245.
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