Stereoselective total synthesis of (+)-goniothalesdiol and (+)-2,5-epi-goniothalesdiol from D-mannitol

Article abstract of DOI:10.1055/s-2007-980351

An efficient and practical total synthesis of (+)-goniothalesdiol and its 2,5-epi analogue is described herein. The key features include a diastereoselective reduction of C-5 keto with Zn(BH₄)₂ to generate the desired stereochemistry

Full text of DOI:10.1055/s-2007-980351

1464
LETTER
Stereoselective Total Synthesis of (+)-Goniothalesdiol and (+)-2,5-epi-
Goniothalesdiol from D-Mannitol
Total
S
ynthesi
u
s
of (+)-Gon
biothalesdiol
h
and (+)-2,5-
e
a
pi
-
Gonioth
salesdiol h Ghosh,* Chapala Nageswara Rao, Samit Kumar Dutta
Division of Organic Chemistry-III, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India
Fax +91(40)27193108; E-mail: subhashbolorg3@yahoo.com
Received 22 February 2007
Our retrosynthetic analysis is shown in Scheme 1. Gonio-
thalesdiol (1) could be synthesized from 3, in three steps:
oxidation, two-carbon Wittig olefination and finally re-
duction of olefin as well as debenzylation under hydroge-
Abstract: An efficient and practical total synthesis of (+)-gonio-
thalesdiol and its 2,5-epi analogue is described herein. The key
features include a diastereoselective reduction of C-5 keto with
Zn(BH4)2 to generate the desired stereochemistry at C-5. The tetra-
hydrofuran backbone of natural goniothalesdiol was synthesized nation conditions. Again 3, in turn, could be obtained
under basic conditions via epoxide formation, followed by in situ 5-
from 4 via terminal epoxide formation followed by in situ
exo opening of the epoxide ring with g-benzoyloxy oxygen upon
5-exo epoxide opening with g-benzoyloxy oxygen with
debenzoylation. For the 2,5-epi analogue, the tetrahydrofuran ring
concomitant debenzoylation under methanolic K2CO3
was formed via acid-catalyzed acetonide deprotection followed by
conditions. Compound 4 could be obtained from 5, which
concomitant SN2 displacement of the O-mesyl group at C-5 center
could be synthesized from D-mannitol (8) according to the
reported procedures.7 The corresponding 2,5-epi-gonio-
thalesdiol (2) could be synthesized from alcohol 6, which
could be obtained from 7 via acid-atalyzed acetonide
deprotection followed by in situ C-5-O-mesyl displace-
ment with C-2-g-oxygen. Compound 7, in turn, could be
synthesized from 5.
with C-2-g-oxygen.
Key words: goniothalesdiol, Zn(BH4)2 reduction, cycloetherifica-
tion, D-mannitol
Many plants of the genus Goniothalamus are well known
sources of important biologically active natural products,
like acetogenins,1 alkaloids,2 styryllactones3 and fla-
vanoids.4 As a result they have attracted attention of many
natural product chemists. In 1994 Goh et al. isolated go-
niothalesdiol (1), a tetrasubstituted tetrahydrofuran, via
bioassay-directed separation of the Goniothalamus born-
eensis tree’s bark extracts5 (Figure 1). It showed strong
cytotoxic activity against P388 mouse leukemia cells and
strong insecticidal activities. The structure and relative
stereochemistry of this compound were determined by a
combination of NMR spectroscopy, MS, chemical trans-
formation and semi-synthesis.5 Due to its potential bioac-
tivities many synthetic methodologies have been
developed and several total syntheses have appeared for 1
and its analogue.6 More facile and practical methods are
still needed in order to access the preparation of this com-
pound and its analogues. Herein, we report a new ap-
proach for the total synthesis of (+)-goniothalesdiol (1)
and its 2,5-epi analogue 2, starting from the inexpensive
starting material, D-mannitol.
OBn
BnO
OBn
BnO
2
1
2
5
5
2
OH
OH
Ph
Ph
O
O
3
6
OMs OBn
OBz OBn
Ph
Ph
OTs
O
O
OBn
OBn OH
7
4
OH OBn
HO
O
O
OBn
5
D-mannitol
8
Scheme 1 Retrosynthetic analysis
HO
OH
HO
OH
5
2
2
5
Thus our synthesis started with 5, which was prepared
from D-mannitol according to the reported procedures.7
Oxidative cleavage of the diol with NaIO4 in THF–H2O
(2:1) at 0 °C afforded aldehyde, which on treatment with
PhMgBr in Et2O at 0 °C gave 9 as an inseparable 70:30
diastereomeric mixture in 56% yield in two steps
(Scheme 2). Oxidation of 9 with 2-iodoxybenzoic acid
(IBX) followed by stereoselective alkoxy-directed keto
reduction with Zn(BH4)2 in THF at –20 °C afforded 10 as
a major isomer in 80% yield in two steps.8 Benzoylation
Ph
COOMe
Ph
COOMe
O
O
(+)-goniothalesdiol
(+)-2,5-epi-goniothalesdiol
1
2
Figure 1
SYNLETT 2007, No. 9, pp 1464–1466
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980351; Art ID: G06507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-Goniothalesdiol and (+)-2,5-epi-Goniothalesdiol
1465
OH OBn
OMs OBn
of the hydroxyl group in 10 with BzCl, Et3N and DMAP
(cat.) in CH2Cl2 gave 11 as a pure diastereomer after crys-
tallization from hexane, in 90% yield. Conversion of 11 to
4 was achieved in two steps. Acetonide deprotection of 11
with CSA in MeOH at 0 °C gave diol, which on regio-
selective tosylation of the primary hydroxyl group with
TsCl and Et3N in CH2Cl2 at 0 °C afforded 4 in 81% yield
from 11.
ii
i
Ph
Ph
O
O
O
OBn
10
O
OBn
7
OBn
BnO
Ph
OBn
BnO
v
iii, iv
OH
2
COOMe
Ph
O
OH OBn
HO
O
6
13
i, ii
ref. 7
O
D-mannitol
O
OBn
5
Scheme 3 Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 0 °C,
30 min, 98%; (ii) CSA, CH2Cl2–MeOH (2:1), 0 °C, 30 min, 92%; (iii)
DMP, CH2Cl2, 0 °C, 30 min; (iv) Ph3P=CHCOOMe, CH2Cl2, r.t., 2 h,
90% in two steps; (v) Pd black (1.2 equiv), 4.4% HCOOH in MeOH,
50 °C, 30 min, 62%.
8
OH OBn
OH OBn
v
iii, iv
Ph
Ph
O
O
O
OBn
O
OBn
9
OBz OBn
10
OBz OBn
acetonide as well as cyclization to form the tetrahydro-
furan 6 with 2,5-cis geometry in 92% yield.10 Finally 6
was converted into 2 following the same set of reactions
as mentioned in Scheme 2 (for 3 → 1). The spectroscopic
and analytical data of 2 were in good agreement with the
literature data.6h,11
viii
vi, vii
Ph
Ph
OTs
O
OBn OH
O
OBn
4
11
BnO
OBn
OBn
BnO
xi
ix, x
1
OH
In conclusion, we have reported a new strategy for the ste-
reoselective total synthesis of natural (+)-goniothalesdiol
(1) and its 2,5-epimer 2 from the commercially available,
inexpensive starting material D-mannitol. The key steps of
our synthetic sequence were the alkoxy-directed diastere-
oselective reduction of ketone with Zn(BH4)2 to instill the
required stereochemistry at C-5 and the cis-2,5-substitu-
tion of the tetrahydrofuran ring was attained via the in situ
epoxide formation followed by the opening of the epoxide
with g-oxygen with concomitant debenzoylation. The cis-
2,5-substituted tetrahydrofuran moiety for 2,5-epi-gonio-
thalesdiol was synthesized via CSA-mediated acetonide
deprotection with concomitant SN2 displacement of the
C-5-O-mesyl group with C-2-oxygen. The preparation of
analogues and study of their biological activities are
currently under progress.
COOMe
Ph
Ph
O
O
3
12
Scheme 2 Reagents and conditions: (i) NaIO4, THF–H2O (2:1),
0 °C, 1 h; (ii) PhMgBr, Et2O, 0 °C, 30 min, 56% in two steps;
(iii) IBX, CH2Cl2–DMSO (3:1), 25 0 °C, 12 h; (iv) Zn(BH4)2, THF,
–20 °C, 12 h, 80% in two steps; (v) BzCl, Et3N, DMAP (cat.), CH2Cl2,
12 h, 92%; (vi) CSA, MeOH–CH2Cl2, r.t.; (vii) TsCl, Et3N, DMAP
(cat.), CH2Cl2, 0 °C to r.t., 6 h, 81% in two steps; (viii) K2CO3,
MeOH, 0 °C to r.t., 12 h, 84%; (ix) DMP, CH2Cl2, 0 °C, 30 min; (x)
Ph3P=CHCOOMe, CH2Cl2, r.t., 2 h, 90% in two steps; (xi) Pd black
(1.2 equiv), 4.4% HCOOH in MeOH, 50 °C, h, 35%.
Compound 4 on treatment with K2CO3 in anhydrous
methanol underwent debenzoylation as well formed
terminal epoxide, which underwent in situ 5-exo opening
with the deprotected g-oxygen to afford the compound 3
in 84% yield. Compound 3 was oxidized with DMP to
give the aldehyde, which on two-carbon Wittig olefina-
tion with Ph3P=CHCOOMe at room temperature afforded
the compound 12 (E/Z = 70:30) in 90% yield. Final depro-
tection of the benzyloxy groups at C-3 and C-4, and re-
duction of the double bond of derivatives (E)-12 and (Z)-
12 were carried out with 1.2 equivalents of Pd (black) in
4.4% HCOOH–MeOH, at 55 °C for 30 minutes to afford
(+)-goniothalesdiol (1) in 35% yield.6a Spectroscopic and
analytical data of 1 were in good agreement with the liter-
ature data.6h,9
Acknowledgment
We are thankful to CSIR (C.N.R, S.K.D.), New Delhi for research
fellowships. We are also thankful to Dr. T. K. Chakraborty, Dr. A.
C. Kunwar and Director, IICT for their support and encouragement.
References and Notes
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For the synthesis of 2,5-epi-goniothalesdiol, we started
with compound 10, which on treatment with MsCl and
Et3N in CH2Cl2 afforded compound 7 in 98% yield.
(Scheme 3) Compound 7 on treatment with CSA in anhy-
drous MeOH resulted in the simultaneous deprotection of
Synlett 2007, No. 9, 1464–1466 © Thieme Stuttgart · New York

1466
S. Ghosh et al.
LETTER
(7) (a) Chakraborty, T. K.; Ghosh, S.; Rao, M. H. V. R.;
(3) (a) El-Zayat, A. A. E.; Ferrigni, N. R.; McCloud, T. G.;
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(9) Spectral Data of Methyl 3-[2S,3S,4R,5R]-3,4-Dihydroxy-5-
phenyltetrahydrofuran-2-yl)propionate (1): [a]D27 +8.1 (c =
0.7, EtOH). IR (neat): 3429, 2951, 1736, 1441 cm–1. 1H
NMR (600 MHz, CDCl3): d = 7.42 (d, J = 7.3 Hz, 2 H), 7.35
(t, J = 7.3 Hz, 2 H, Ar), 7.29 (d, J = 7.3 Hz, 1 H), 4.60 (d,
J = 4.6 Hz, 1 H), 4.04–4.10 (m, 3 H), 3.70 (s, 3 H), 2.63 (dt,
J = 6.7, 17.1 Hz, 1 H), 2.51 (ddd, J = 6.7, 8.1, 17.1 Hz, 1 H),
2.12 (m, 1 H) 2.06 (dq, J = 6.7, 14.3 Hz, 1 H). 13C NMR (150
MHz, CDCl3): d = 174.9, 139.7, 128.5, 127.8, 126.1, 85.9,
85.0, 80.7, 78.7, 52.0, 30.5, 23.4. MS (LCMS): m/z = 289 [M
+ Na]+.
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epimers, see: (c) Babjak, M.; Kapitán, P.; Gracza, T.
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(11) Spectral Data of Methyl 3-[2R,3S,4R,5S]-3,4-Dihydroxy-5-
phenyltetrahydrofuran-2-yl)propionate (2): [a]D27 +94.47
(c = 0.38, EtOH). IR (neat): 3420, 2951, 1724, 1440 cm–1. 1H
NMR (600 MHz, CDCl3): d = 7.30–7.40 (m, 5 H), 5.14 (d,
J = 3.5 Hz, 1 H), 4.11 (dd, J = 1.2, 3.5 Hz, 1 H), 4.06 (dd,
J = 1.2, 3.3 Hz, 1 H), 3.89 (ddd, J = 3.3, 6.2, 7.0 Hz, 1 H),
3.70 (s, 3 H), 2.52–2.64 (m, 2 H), 2.11–2.15 (m, 2 H). 13
C
NMR (150 MHz, CDCl3): d = 174.2, 135.6, 128.6, 128.1,
126.8, 84.7, 82.9, 81.7, 80.1, 51.8, 30.6, 28.7. MS (LCMS):
m/z = 289 [M + Na]+.
Synlett 2007, No. 9, 1464–1466 © Thieme Stuttgart · New York