A concise total synthesis of cleistenolide

Article abstract of DOI:10.1016/j.tetasy.2016.06.012

A concise total synthesis of cleistenolide has been achieved from D-glucose. The synthesis of cleistenolide proceeds in six steps from D-glucose diacetonide in 42.5% overall yield. Selective benzoylation and Still-Gennari olefination are the key reactions involved in the synthesis.

Full text of DOI:10.1016/j.tetasy.2016.06.012

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
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A concise total synthesis of cleistenolide
⇑
A. Bal Reddy, B. Kumara Swamy, Jhillu Singh Yadav
Centre for Semiochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of cleistenolide has been achieved from D-glucose. The synthesis of cleistenolide
Received 1 June 2016
Accepted 17 June 2016
Available online xxxx
proceeds in six steps from
D-glucose diacetonide in 42.5% overall yield. Selective benzoylation and Still-
Gennari olefination are the key reactions involved in the synthesis.
Ó 2016 Published by Elsevier Ltd.
1. Introduction
The synthesis of target molecule 1 began with commercially
available
D-glucose diacetonide 5. The selective acetonide depro-
Cleistochlamys kirkii Oliver extracts are used as a remedy in tra-
ditional medicine for treatment of wound infections, rheumatism,
and tuberculosis.1 In 2007, Nkunya et al. reported on two novel
constituents; cleistenolide and cleistodienol, from the plant
extracts of the Cleistochlamys kirkii Oliver2 family of Annonaceae.
Cleistenolide exhibit a wide range of biological activities such as
antibacterial activity against Staphylococcus aureus and Bacillus
anthracis, and antifungal activity against Candida albicans (Fig. 1).3
There are several reports on the total synthesis of cleistenolide4
using different methods such as ring closing metathesis, selective
acylation, cis-olefination,4a,c Yamaguchi lactinization4b mixed
hydride reduction and Still-Gennari olefination4e as the key steps.
As part of our longstanding interest in the synthesis of bioactive
natural products, we have taken up the total synthesis of cleisteno-
lide. Recently we reported5 the synthesis of cleistenolide from
tection of D-glucose diacetonide 5 with 60% acetic acid and water
over 8 h gave triol 6 in 85% yield. Selective benzoylation6 with ben-
zoyl chloride using dibutyltin oxide complex in the presence of a
catalytic amount of DMAP afforded 7 in 72% yield.
Compound 7 was converted into diacetylated 4 by using acetic
anhydride and pyridine in DCM at 0 °C for 2 h to furnish compound
4 in 92% yield. Compound 4 was further treated with trifluoroacetic
acid and water (2:1) at 25 °C for 3 h to give the product in 95% yield
as a 12:1 epimeric mixture of lactol 8. Oxidative cleavage of 8 with
sodium periodate7 in an acetone and water mixture gave aldehyde
3. Aldehyde 3 was subjected directly to a one pot homologation
followed by lactonization reaction using Still-Gennari8 olefination
conditions to achieved the title compound (À)-cleistenolide 1 in
82% overall yield (Scheme 2). The physical and spectroscopic data
25
([a] ,
1H and 13C NMR.) of compound 1 were identical with the
D
commercially available
D-mannitol. Herein, we report short syn-
reported data in the literature.4
thesis of cleistenolide in 6 steps without changing chiral centers
present in the starting material, D-glucose diacetonide.
3. Conclusion
2. Results and discussion
In summary, we have demonstrated the concise, efficient and
economic synthetic route for the total synthesis of cleistenolide.
The key steps involved in this synthesis are selective benzoylation
and Still-Gennari olefination. The total synthesis of cleistenolide
has been achieved in six steps with an overall yield of 42.5%.
The retrosynthetic analysis (À)-cleistenolide indicated that it
could be synthesized by cis-olefination followed by lactonization
with the corresponding aldehyde 3. Aldehyde 3 can be prepared
from compound 4 via selective acetonide deprotection followed
by cleavage of the diol using NaIO4. Diacetylated compound 4
4. Experimental
4.1. General
can be easily accessed from compound 5 (D-glucose diacetonide)
by selective acetonide deprotection, and benzoylation6 using a
dibutyltinoxide complex with a catalytic amount of DMAP and
acetic anhydride (Scheme 1).
Air and/or moisture sensitive reactions were carried out in
anhydrous solvents under an argon atmosphere in an oven or
flame-dried glassware. All anhydrous solvents were distilled prior
to use: THF, from Na and benzophenone; CH2Cl2, DMSO from CaH2.
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@gmail.com (J.S. Yadav).
http://dx.doi.org/10.1016/j.tetasy.2016.06.012
0957-4166/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Reddy, A. B.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.06.012

2
A. B. Reddy et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
OBz
OAc
OH
Chemical shifts (d) are given in ppm relative to TMS and coupling
constants (J) in Hz. Mass spectra were obtained on an Exactive
Thermo Scientific Orbitrap Mass Spectrometer. The following
abbreviations are used to designate signal multiplicity: s = singlet,
d = doublet, dd = doublet of doublet, t = triplet, td = triplet of dou-
ble, q = quartet, m = multiplet, br = broad.
OAc
AcO
O
O
O
O
AcO
(−)-cleistenolide 1
(−)-cleistodienol 2
Figure 1.
4.2. (R)-1-((3aR,5R,6S,6aR)-6-Hydroxy-2,2-dimethyl tetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol 6
D
-Glucose diacetonide 5 (10 g 38.4 mmol) was dissolved in a
OAc
mixture of acetic acid (100 mL) and water (50 mL). The mixture
was stirred for 12 h at 25 °C. The crude was concentrated under
vacuum at 50 °C. A pure compound was obtained by recrystalliza-
O
OAc
O
O
O
O
OH
O
AcO
O
tion from ethyl acetate to give triol compound
6 (7.2 g,
AcO
20 = À11.2 (c 1.1, H2O); IR (KBr): 3420, 2952,
3
cleistenolide 1
32.64 mmol, 85%).[
a]
D
2795, 1434, 1322, 1275, 1235, 1095, 1043 cm–1
.
1H NMR
(300 MHz, CD3OD): d 1.32 (s, 3H), 1.47 (s, 3H), 3.62 (dd, J = 6.0,
11.7 Hz, 1H), 3.79 (dd, J = 3.0, 11.8 Hz, 1H), 3.90–3.94 (m, 1H),
4.04 (dd, J = 2.6, 8.3 Hz, 1H), 4.22 (d, J = 2.3 Hz, 1H), 4.51 (d,
J = 3.4 Hz, 1H), 5.90 (d, J = 3.4 Hz, 1H). 13C NMR (75 MHz, CD3OD):
d 26.4, 27.0, 65.3, 70.4, 75.5, 81.3, 86.5, 106.4, 112.7. HRMS (ESI-
MS): m/z [M+Na]+ calcd for C9H16O6Na: 243.0845; found:
243.0850.
AcO
O
O
O
O
O
O
O
O
O
O
AcO
HO
4
D
-glucose diacetonide 5
4.3. (R)-2-Hydroxy-2-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethyl benzoate 7
Scheme 1. Retrosynthetic analysis of (À)-cleistenolide 1.
To a mixture of Bu2SnO (7.92 g, 31.8 mmol) and triol compound
6 (7.0 g, 31.8 mmol) dry methanol (210 mL) was added. The mix-
ture was heated at reflux for 10 h. The solvent was evaporated
and residue was dried under vacuum. The crude product was dis-
solved in 1,4-dioxane (210 mL), after which were added benzoyl
chloride (4.92 g, 35.0 mmol) and DMAP (0.1 mol equiv). The mix-
ture was left for 12–16 h and the reaction was monitored by TLC.
The mixture was concentrated in vacuo at 40 °C. The tin com-
pounds were removed on silica gel column chromatography by
eluting with CHCl3, and a pure compound was obtained by ethyl
acetate elute to give mono 6-O-benzoylated 7 7.4 g (22.9 mmol,
O
HO
O
O
O
HO
60% AcOH
8 h, 85%
O
O
O
O
HO
HO
5
6
HO
Bu2SnO, MeOH
reflux, 10 h
O
BzO
Ac2O, pyridine
CH2Cl2 , 0 oC 2 h 92%
O
BzCl, dioxane, 72%
72%). [
a]
20 = +7.1 (c 1.05, CHCl3); IR (KBr): 3485, 2952, 2795,
D
O
HO
1690, 1275, 1235, 1075, 1029 cm–1
.
1H NMR (300 MHz, CDCl3): d
7
1.32 (s,3H), 1.48 (s, 3H), 3.11 (d, J = 3.8 Hz, 1H), 3.20 (d,
J = 3.2 Hz, 1H), 4.19 (dd, J = 3.0, 6.8 Hz, 1H), 4.33–4.40 (m, 1H),
4.41–4.43 (m, 1H), 4.50 (dd, J = 6.04, 11.3 Hz, 1H), 4.56 (d,
J = 3.78, 1H), 5.99 (d, J À3.8, 1H), 7.45 (t, J = 7.4, 2H), 7.57 (t,
J = 7.4 Hz, 1H), 8.05 (d, J = 7.1 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d 24.9, 25.5, 66.0, 66.5, 73.3, 79.3, 84.5, 104.5, 111.0, 127.6,
128.8, 132.4, 132.8, 166.4. HRMS (ESI-MS): m/z [M+H]+ calcd for
AcO
AcO
O
O
TFA, H2O (2:1)
95%
BzO
BzO
O
OH
OH
O
AcO
AcO
8
4
OAc
OH
MeO2CCH2P(O)(OCH2CF3)2
NaH, THF
BzO
NaIO4, acetone, H2O
C16H21O7: 325.1287; found: 325.1281.
O
-78 oC, 1 h 82% (2 steps)
AcO
4.4. (R)-2-Acetoxy-2-((3aR,5R,6S,6aR)-6-acetoxy-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethyl benzoate 4
3
OAc
O
O
O
O
Pyridine (4.87 g. 61.6 mmol) was added to a stirred solution of
mono 6-O-benzoylated 7 (5.0 g, 15.4 mmol) and CH2Cl2 (50.0 mL)
at 0 °C. The mixture was stirred at 0 °C for 10 min, after which
Ac2O (3.93 g, 38.5 mmol) was added to the mixture at 0 °C and stir-
red for 2 h at 0 °C. The reaction was monitored by TLC, and the sol-
vents were removed under vacuum at 40 °C. The residue was
dissolved in CH2Cl2 (50.0 mL) and sat. NaHCO3 solution (30 mL)
was added. Organic layer was separated and concentrated under
reduced pressure. The crude was subjected to column chromatog-
raphy by eluting with hexanes and ethyl acetate obtained 5.75 g of
AcO
1
Scheme 2. Total synthesis of (À)-cleistenolide 1.
Commercial reagents were used without purification. Column
chromatography was carried out by using ACME silica gel
(60–120 mesh). Optical rotations [a] .
Infrared spectra were recorded in CHCl3/neat (as specified) on
Perkin-Elmer 683 spectrometer. 1H and 13C NMR spectra were
recorded on a Varian Unity-500 or a Bruker-300 spectrometer.
are given in 10À1 ° cm2 gÀ1
D
compound 4 (14.1 mmol, 92%). [
(KBr): 3465, 2932, 2791, 1690, 1685, 1670, 1097, 1042 cm–1
NMR (300 MHz, CDCl3): d 1.32 (s, 3H), 1.53 (s, 3H), 2.01 (s, 3H),
a]
20 = +5.6 (c 1.01, CHCl3); IR
D
.
1H
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A. B. Reddy et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
2.08 (s, 3H), 4.40 (dd, J = 6.0, 12.1 Hz, 1H), 4,52 (d, J = 3.8 Hz, 1H),
4.55 (d, J = 3.0 Hz, 1H), 4.80 (dd, J = 2.3, 12.8 Hz, 1H), 5.35–5.47
(m, 2H), 5.96, (d, J = 3.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53–7.60
(t, J = 7.6 Hz, 2H), 8.03 (d, J = 7.1 2H). 13C NMR (75 MHz, CDCl3): d
20.7, 20.8, 26.2, 26.7, 64.0, 67.5, 74.8, 76.8, 83.2, 105.1, 112.5,
128.4, 129.6, 129.7, 133.1, 166.1, 169.6, 169.8. HRMS (ESI-MS):
m/z [M+H]+ calcd for C20H25O9: 409.1499; found: 409.1494.
was then added and the compound was extracted with ethyl acet-
ate (2 Â 10 mL). Pure product was obtained by column chromatog-
raphy by eluting with hexanes and ethyl acetate to afford 0.075 g
of compound 1 (0.22 mmol, 82%). Mp 132–134 °C. [
a]
25 = À153.1
D
(c 0.8, CHCl3); IR (neat): 2975, 1739, 1475, 1385, 1260, 1115,
1045, 752 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.04 (s, 3H), 2.09
.
(s, 3H),4.52 (dd, J = 4.5, 12.7 Hz, 1H), 4.80 (dd, J = 2.5, 9.6 Hz, 1H),
4.92 (dd, J = 2.3, 12.7 Hz, 1H), 5.41 (dd, J = 2.6, 6.0 Hz, 1H), 5.51
(ddd, J = 2.3, 4.4, 9.6 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 7.00 (dd,
J = 6.0, 9.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H),
8.01 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 20.5, 20.7,
59.7, 62.1, 67.7, 75.6, 125.4, 128.4, 129.6, 129.7, 133.2, 139.8,
161.1, 165.9, 169.5, 169.8. ESI-MS: m/z: 363 (M+H)+. HRMS calcd
for C18H19O8: 363.1080; found: 363.1089.
4.5. (R)-2-Acetoxy-2-((2R,3R,4R,5S)-3-acetoxy-4,5-dihydroxytet-
rahydrofuran-2-yl)ethyl benzoate 8
A solution of compound 4 (0.9 g, 2.2 mmol) in a mixture of TFA:
H2O (2:1, 27 mL) was stirred at 25 °C for 3 h, and monitored by TLC.
TFA was evaporated under reduced pressure and codistilled with
benzene to afford 0.77 g of compound
8 as a thick syrup
(2.09 mmol, 95%). 1H NMR (300 MHz, CDCl3): d 2.01 (s, 3H), 2.08
(s, 3H), 4.10 (m, 1H), 4.40 (dd, J = 6.04, 12.8 Hz, 1H), 4.58 (dd,
J = 3.8, 9.1 Hz, 1H), 4.76 (dd, J = 2.7, 12.1 Hz, 1H), 5.21–5.40 (m,
2H), 5.56 (d, J = 4.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.53–7.60 (m,
1H), 8.02 (d, J = 6.8 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 20.6,
20.8, 26.4, 26.7, 64.2, 67.4, 74.8, 76.7, 83.2, 105.2, 128.4, 129.7,
129.8, 133.1, 166.3, 169.7, 169.8. HRMS (ESI-MS): m/z [M+Na]+
calcd for C17H20O9Na: 391.1006; found: 391.1004.
Acknowledgements
A.B.R thanks CSIR, New Delhi, India for the award of fellowship.
J. S. Y. thanks CSIR, New Delhi, India and the Department of Science
and Technology (DST), New Delhi, India, for the award of Bhatnagar
and J. C. Bose Fellowships. The authors also acknowledge CSIR for
funding from 12th Five Year plan project ORIGIN (CSC-108).
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