Synthesis of four diastereomers and structural revision of tetradenolide

Article abstract of DOI:10.1016/j.tetlet.2014.05.109

Four diastereomers of tetradenolide, a cytotoxic α-pyrone isolated from Tetradenia riparia, were synthesized stereoselectively using the Z-selective Horner-Emmons reaction followed by acid catalyzed lactonization. Making comparison of the ¹H an

Full text of DOI:10.1016/j.tetlet.2014.05.109

Accepted Manuscript
Synthesis of four diastereomers and structural revision of tetradenolide
Maki Tokuda, Yuji Kurogome, Rieko Katoh, Yukie Nohara, Yasunao Hattori,
Hidefumi Makabe
PII:
S0040-4039(14)00940-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.109
TETL 44700
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
16 April 2014
22 May 2014
28 May 2014
Please cite this article as: Tokuda, M., Kurogome, Y., Katoh, R., Nohara, Y., Hattori, Y., Makabe, H., Synthesis of
four diastereomers and structural revision of tetradenolide, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.05.109
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Synthesis of four diastereomers and structural revision of
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Maki Tokuda, Yuji Kurogome, Rieko Katoh, Yukie Nohara, Yasunao Hattori, and Hidefumi Makabe*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Synthesis of four diastereomers and structural revision of tetradenolide
Maki Tokuda,b Yuji Kurogome,a Rieko Katoh,a Yukie Nohara,b Yasunao Hattori,c and Hidefumi Makabea∗
aGraduate School of Agriculture, Sciences of Functional Foods, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano, 399-4598, Japan
bDepartment of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano, 399-4598, Japan
cDepartment of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Four diastereomers of tetradenolide, a cytotoxic α-pyrone isolated from Tetradenia riparia,
were synthesized stereoselectively using Z-selective Horner-Emmons reaction followed by acid
catalyzed lactonization. Making comparison of the 1H and 13C NMR spectral data of the four
diastereomers with those of the reported value of natural product did not lead to determine the
relative stereochemistry of the natural tetradenolide. Thus detailed investigation of the spectral
data of the related compounds led us to revise the structure of tetradenolide as
deacetylboronolide.
Received in revised form
Accepted
Available online
Keywords:
tetradenolide
α-pyrone
2009 Elsevier Ltd. All rights reserved.
structural revision
total synthesis
O
O
Tetradenolide is an antimicrobial, phytotoxic and cytotoxic α-
pyrone isolated by Luc Van Puyvelde and De Kimpe from
1
O
OH
O
OH
Tetradenia
riparia.1
The
related
compound
(+)-
1'
6
2'
deacetylboronolide was isolated Luc Van Puyvelde and co-
workers from the same plant, Tetradenia riparia (Hochst) N. E.
Br. (Labiatae)2 and (+)-boronolide was isolated from Tetradenia
fruticosa Benth and Tetradenia barbera (N. E. Br.) Codd,
respectively.3,4 As to the biological activity of boronolides, anti-
malarial activity was reported (Figure 1).2,5 Many reports of the
syntheses of (+)-boronolide and (+)-deacetylboronolide have
been published so far.6 However, synthetic study of teradenolide
has not been reported yet. The reported structure of tetradenolide
was shown in Figure 1 and the relative stereochemistry and
optical rotation value of this compound were not reported.1
OH
OH
S
S
R
R S R
(6 ,1' ,2' )-tetradenolide (1a)
(6 ,1' ,2' )-tetradenolide (1b)
O
O
O
OH
O
OH
OH
OH
(6R,1'R,2'R)-tetradenolide (1d)
S
R R
(6 ,1' ,2' )-tetradenolide (1c)
Figure 2. The structures of four diastereomers of tetradenolide.
At first we began to synthesize (6S,1’S,2’R)-tetradenolide (1a)
starting from 1,3-propanediol (2). Mono-protection of 1,3-
propanediol (2) with benzyl bromide in the presence of NaH
followed by oxidation with SO3・pyridine afforded aldehyde 3.
Alkylation of the 1-hexyne with aldehyde 3 using n-BuLi gave 4
which was subjected to reduction with LiAlH4 in THF under
reflux to furnish E-allylic alcohol 5. Oxidation of 5 with Dess-
Martin periodonane led to enone 6.7 Enone 6 was subjected to the
Sharpless asymmetric dihydroxylation using AD mix β to give
diol 7 in 97% ee analyzed by Mosher ester derivative.8 Protection
of the resulting diol with 2,2-dimethoxypropane in the presence
of PPTS afforded 8. Reduction of the ketone 8 with L-Selectride
gave 9 in a single diastereomer.9 To confirm the stereochemistry
of newly formed oxymethine carbon, advanced Mosher method
was used (supplementary content).10 We confirmed that this
carbinol center possessed S configuration. Secondary hydroxy
Figure 1. The reported structure of tetradenolide and related
compounds.
The synthesis of the four diastereomers and making comparison
1
of their H and 13C NMR spectral data with those of natural
tetradenolide would be
a crew to determine its relative
stereochemistry. Therefore we planned to synthesize four
diastereomers of tetradenolide (Figure 2).
———
∗ Corresponding author. Tel. +81 265 77 1630; fax +81 265 77 1700; e-mail: makabeh@shinshu-u.ac.jp

2
Tetrahedron Letters
group of 9 was protected as ethoxyethoxy group to afford 10
epoxide 19. Alkylation of 19 using C3H7MgCl in the presence of
CuI gave 20. Protection of the resulting secondary hydroxy group
as MOM ether followed by hydroboration using 9-BBN and
treatment with NaOH and H2O2 furnished 21. Compound 21 was
converted to (6S,1’R,2’R)-tetradenolide (1c) as described in the
synthesis of 1a (Scheme 3).
subsequent removal of benzyl group with Na in liquid NH3
followed by oxidation with Dess-Martin periodonane furnished
aldehyde 11. The resultant aldehyde 11 was subjected to Z-
selective
Horner-Emmons
reaction
using
diphenyl
phosphonoacetate to afford 12 with 1:19 of E:Z ratio.11 Finally,
12 was treated with acid in THF-H2O under reflux to give
(6S,1’S,2’R)-tetradenolide (1a) (Scheme 1).
Scheme 3. Synthesis of (6S,1’R,2’R)-tetradenolide (1c). Reagents
and conditions: (a) (i) H2SO4, acetone, (ii) CH3P+Ph3I−, t-BuOK,
71%; (b) (i) TrisCl, pyridine; (ii) NaH, 63%; (c) C3H7MgCl, CuI;
69%; (d) (i) MOMCl, i-Pr2NEt, (ii) 9-BBN, NaOH, H2O2; 44%; (e)
(i) Dess-Martin periodinane, (ii) (PhO)2P(O)CH2CO2Et, NaH, 30%;
(f) HCl, THF-H2O, 60%
Scheme 1. Synthesis of (6S,1’S,2’R)-tetradenolide (1). Reagents and
conditions: (a) (i) BnBr, NaH, NaI, (ii) SO3・pyridine, DMSO, 35%;
(b) n-BuLi, 1-hexyne, 90%; (c) LiAlH4, THF reflux, 77%; (d) Dess-
Martin periodinane, 68%; (e) AD mixβ, MeSO2NH2, 78%; (f) 2,2-
dimethoxypropane, PPTS, quant.; (g) L-Selectride, 90%; (h) ethyl
vinyl ether, PPTS, 96%; (i) (i) Na, NH3, (ii) Dess-Martin periodinane,
60%; (j) (PhO)2P(O)CH2CO2Et, NaH, 66%; (k) HCl, THF-H2O, 51%
Next, we began to synthesize (6R,1’R,2’R)-tetradenolide (1d).
Alkylation of 4-butyn-1-ol (23) with 1-pentanal (24) using n-
BuLi gave 25 which was subjected to reduction with LiAlH4 in
THF under reflux to furnish E-allylic alcohol 26. Protection of
the primary hydroxy group of 26 with TBDPSCl in the presence
of Et3N and DMAP afforded 30. Oxidation of the secondary
hydroxy group of 27 with Dess-Martin periodinane gave enone
28. Enone 28 was subjected to the Sharpless asymmetric
dihydroxylation using AD mix β to give diol 29 in 97% ee
analyzed by Mosher ester derivative.8 Protection of the resulting
diol with 2,2-dimethoxypropane in the presence of PPTS
afforded 30. Reduction of the ketone 30 with L-Selectride gave
31. To confirm stereochemistry of the newly formed oxymethine
carbon, advanced Mosher method was used and this carbinol
center was confirmed to be S configuration (supplementary
content).10 The secondary hydroxy group of 31 was inverted
using Mitsunobu reaction with p-nitrobenzoic acid in the
presence of DEAD and PPh3. Hydrolysis of p-nitrobenzoyl ester
with methanolic NaOH gave 32. Protection of the resulting
secondary hydroxy group as MOM ether followed by
deprotection of the TBDPS group using TBAF gave 33
Compound 33 was converted to (6R,1’R,2’R)-tetradenolide (1d)
as described in the synthesis of 1a (Scheme 4).
Synthesis of (6R,1’S,2’R)-tetradenolide (1b) was started from 9
which was an intermediate for the synthesis of 1a. The secondary
hydroxy group of 9 was inverted using Mitsunobu reaction with
p-nitrobenzoic acid in the presence of DEAD and PPh3.12
Hydrolysis of p-nitrobenzoyl ester with methanolic NaOH gave
13. Compound 13 was converted to (6R,1’S,2’R)-tetradenolide
(1b) as described in the synthesis of 1a (Scheme 2).
Scheme 2. Synthesis of (6R,1’S,2’R)-tetradenolide (1b). Reagents
and conditions: (a) (i) p-NBA, DEAD, PPh3, (ii) NaOH, MeOH,
85%; (b) ethyl vinyl ether, PPTS, 96%; (c) (i) Na, NH3, (ii) Dess-
Martin periodinane, 60%; (d) (PhO)2P(O)CH2CO2Et, NaH, 66%; (k)
HCl, THF-H2O, 55%.
Synthesis of (6S,1’R,2’R)-tetradenolide (1c) was started from D-
ribose (17).13 Protection of the diol at 2,3-position with acetone in
the presence of sulfric acid followed by Wittig reaction with
CH3P+Ph3I− afforded diol 18. Introduction of the triisopropyl
benzenesulfonyl (Tris) group at primary hydroxy group under
basic condition followed by treating with NaH gave terminal

3
detail.16 We found that the signals of 13C NMR at C-1’ and C-2’
positions of deacetylboronolide were completely overlapped
using HMQC experiment.16 Therefore, it was possible that the
13C NMR of deacetylboronolide was misread as tetradenolide.1
As to the EI-MS spectrum of natural tetradenolide, Puyvelde et al.
reported that M+ could not be observed. We also measured EI-
MS spectra of 1a-1b and found that only tiny signals of M+ were
observed. Puyvelde et al. prepared bis-O-TMS derivative of
natural tetradenolide and reported that M+ (358, 0.2%) was
observed at 70 eV.1 We prepared bis-O-TMS derivative of 1b
using bis(trimethylsilyl)acetamide (BSA) and measured EI-MS at
70eV (Figure 4). However, M+ (358, 0.2%) was not detected but
(M−Me)+ (343), (M−C4H9)+ (301), and (M−C4H9−2Me)+ (272)
were observed. The pattern of fragmentation was different from
that of reported one of natural tetradenolide derivative.1 We also
prepared tris-O-TMS derivative of (+)-deacetylboronolide and
measured EI-MS at 70 eV.1 As Puyvelde et al. reported, m/z 358
(0.2%) was observed and the pattern of fragmentation was
similar to that of natural tetradenolide derivative except that the
signals of (M−Me)+ (445), (M−C4H9)+ (403), and
(M−C4H9−2Me)+ (374) were observed.
Scheme 4. Synthesis of (6R,1’R,2’R)-tetradenolide (1d). Reagents
and conditions: (a) n-BuLi, 64%; (b) LiALH4, THF reflex, 69%; (c)
TBDPSCl, Et3N, DMAP, 88%; (d) Dess-Martin periodinane, 83%;
(e) AD mixβ, MeSO2NH2, 84%; (f) 2,2-dimethoxypropane, PPTS,
89%; (g) L-Selectride, 96%; (h) (i) p-NBA, DEAD, PPh3, (ii) NaOH,
MeOH, 73%; (i) (i) MOMBr, i-Pr2NEt, (ii) TBAF, 93%; (j) (i) Dess-
Martin periodinane, (ii) (PhO)2P(O)CH2CO2Et, NaH, 44%; (k) HCl,
THF-H2O, 75%.
As to the compounds 1a and 1b, structurally similar
compounds 35 and 36 were synthesized by Rúveda and co-
workers who described the stereoselective transformation of the
naturally abundant argentilactone in 1988.14 The 13C NMR
spectral data of carbinol centers of 1a and 1b were quite similar
to those of 35 and 36, respectively (Figure 3).
O
O
O
OH
BSA
O
OTMS
OH
OTMS
bis-O-TMS 1b
(6R,1'S,2'R)-tetradenolide (1b)
O
O
O
OH
BSA
O
OTMS
OH OH
Figure 3. The related compounds 35 and 36 which were synthesized
by Rúveda and co-workers.
TMSO
OTMS
O
tris- -TMS deacetylboronolide
deacetylboronolide
As four diastereomers of tetradenolide were in hand, we
compared their spectral data with those of the reported values to
determine the relative stereochemistry. As to the 1H NMR spectra,
it is rather difficult to compare because the range of the chemical
shifts of reported 1H NMR spectra had a wide range (see
supplementary information). Thus we focused on analyzing 13C
NMR spectra. The chemical shifts of 13C NMR of natural one and
synthetic 1a-1d were different especially C-6 and C-2’ carbons.
Therefore we could not determine the relative stereochemistry of
tetradenolide (Figure 4).
Figure 5. Preparation of TMS derivatives of 1b and (+)-
deacetylboronolide.
Next, we measured CI-MS spectra of 1a-1d and (+)-
deacetylboronolide. We could observe (M+H)+ clearly. We found
that CI-MS was effective to obtain satisfied data for hydroxylated
δ-lactones. The melting point value of reported tetradenolide was
(102.8-103oC) also very close to that of (+)-deacetylboronolide
o
synthesized by us (101-102 C16) lit.{ (99-100oC,2a 101oC17)}.1
The sample of natural tetradenolide and its spectral data are no
longer available,18 however, it is highly possible that the structure
of tetradenolide is (+)-deacetylboronolide from reasons as
follows: 1) 13C NMR spectral data of natural tetradenolide was
identical with those of (+)-deacetylboronolide; 2) The melting
point value of natural tetradenolide was very close to that of (+)-
deacetylboronolide; 3) natural tetradenolide and (+)-
deacetylboronolide were isolated from the same plant, Tetradenia
riparia.1,2
In conclusion, four diastereomers of tetradenolide, a cytotoxic
α-pyrone isolated from Tetradenia riparia, were synthesized.
The1H and 13C NMR spectral data of the four diastereomers were
not consistent with those of reported values of natural
tetradenolide. The detailed investigation of the 13C NMR data and
melting point data of the related compounds led us to revise the
structure of tetradenolide as (+)-deacetylboronolide.
Figure 4. The difference of chemical shifts of 13C NMR data of
synthetic 1a-1d and natural tetradenolide at C-6 and C-2’ position.
Thus we carefully examined the 13C NMR data of the related
compounds of tetradenolide.2 We noticed that the 13C NMR data
of deacetylboronolide synthesized by Trost and co-worker were
quite similar to those of tetradenolide (Table 1).15 Thus we
synthesized deacetylboronlide to examine its 13C NMR spectra in

4
Tetrahedron
Table 1. 13C NMR data of tetradenolide and (+)-deacetylboronolide
position
tetradenolide
164.02
120.95
146.11
25.79
position
(+)-deacetylboronolide (Trost et al.)a
(+)-deacetylboronolide (by us)
2
3
4
5
6
2
163.98
164.10
3
120.90
120.84
4
146.09
146.21
5
25.75
25.73
77.16
6
77.12
77.15
1’
2’
3’
4’
5’
6’
7’
76.74 (overlapped with solvent)
74.24 (overlapped with 2’ carbon)
1’
2’
3’
4’
5’
6’
74.36
70.20
33.46
27.67
22.62
14.00
74.30
70.14
33.42,
27.64
22.59
13.98
74.24 (overlapped with 1’ carbon)
70.20
33.36
27.64
22.59
13.99
aTrost and co-worker reported that the peak at 76.74 ppm was observed.15
However, we could not observe this signal in the HMQC spectrum and found
that both of C1’ and C-2’ signals were overlapped at 74.24 ppm.16.
13. (a) Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Terahedron 2009,
65, 6304; (b) Srihari, P.; Kumaraswamy, B.; Rao, G. M.; Yadav, J.
S. Terahedron: Asymmetry 2010, 21, 106.
14. Signorella, S. R.; Cravero, R. M.; Sala, L. F.; Rúveda, E. A. Synth.
Commun. 1988, 18, 1935.
Acknowledgments
15. Trost, B. M.; Yeh, V. S. C. Org. Lett. 2002, 4, 3513.
16. Kurogome, Y.; Hattori, Y.; Makabe, H. Tetrahedron Lett. 2014,
55, 2822.
We thank Prof. Dr. De Kimpe, N. for his valuable information
about α-pyrone natural products. This work was supported in part
by JSPS KAKENHI Grant Number 24580160 to H. M.
17. Chandrasekhar, M.; Chandra, K. L.; Singh, V. K. J. Org. Chem.
2003, 68, 4039.
18. Personal communication with Prof. Dr. De Kimpe, N.
References and notes
Supplementary Material
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Domisse, R. A.; Esmans, E. L.; Van Schoor, O.; Vlietinck, A.
Phytochemistry 1979, 18, 1215; (b) Van Puyvelde, L.; De Kimpe,
N.; Dube, S.; Chagnon-Dube, M.; Boily, Y.; Borremans, F.;
Schamp, N.; Anteunis, M. J. O. Phytochemistry 1981, 20, 2753.
3. Franca, N. C.; Polonsky, J. C. R. Hebd. Seances, Acad. Sci., Ser.
C. 1971, 273, 439.
Supplementary material associated with this article can be
found in the online version at doi:
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(m) Yamauchi, S. ; Isozaki, Y.; Nishimura, Y.; Tsuda, H.;
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Tetrahedron Lett. 2014, 55, 1398.
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5
Graphical Abstract
Synthesis of four diastereomers and structural revision of tetradenolide
Maki Tokuda, Yuji Kurogome, Rieko Katoh, Yukie Nohara, Yasunao Hattori, and Hidefumi Makabe*