Synthesis of botryolide E, ophiocerins A, B and C from D-glucono-δ-lactone

Article abstract of DOI:10.1016/j.tetlet.2020.151960

A concise synthesis of a chiral hexane-tetraol intermediate is achieved from D-glucono-δ-lactone in 6 steps featuring the successively selective deoxygenation. The versatile intermediate can be easily converted into the γ-lactone compound botryolide E and tetrahydropyran derivative ophiocerins A-C respectively. In addition, the direct transformation of ophiocerin C to ophiocerins A and B by Mitsunobu reaction was studied for the first time.

Full text of DOI:10.1016/j.tetlet.2020.151960

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Synthesis of botryolide E, ophiocerins A, B and C from D-glucono-δ-lactone
Faling Zhou, Xiaojing Liu, Yuanliang Jia, Yue Hu, Guiyin Luo, Xiaochuan
Chen
PII:
S0040-4039(20)30403-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151960
TETL 151960
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 March 2020
15 April 2020
19 April 2020
Please cite this article as: Zhou, F., Liu, X., Jia, Y., Hu, Y., Luo, G., Chen, X., Synthesis of botryolide E,
ophiocerins A, B and C from D-glucono-δ-lactone, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/
j.tetlet.2020.151960
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Synthesis of botryolide E, ophiocerins A, B
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and C from D-glucono--lactone
Faling Zhou, Xiaojing Liu, Yuanliang Jia, Yue Hu, Guiyin Luo and Xiaochuan Chen*

1
Tetrahedron Letters
Synthesis of botryolide E, ophiocerins A, B and C from D-glucono--lactone
Faling Zhou, Xiaojing Liu, Yuanliang Jia, Yue Hu, Guiyin Luo and Xiaochuan Chen
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise synthesis of a chiral hexane-tetraol intermediate is achieved from D-glucono--
lactone in 6 steps featuring the successively selective deoxygenation. The versatile intermediate
can be easily converted into the -lactone compound botryolide E and tetrahydropyran derivative
ophiocerins A-C respectively. In addition, the direct transformation of ophiocerin C to
ophiocerins A and B by Mitsunobu reaction was studied for the first time.
Available online
Keywords:
Botryolide E
Ophiocerin
-Lactone
2009 Elsevier Ltd. All rights reserved.
Tetrahydropyran
1. Introduction
Tetrahydropyrans [1] and -lactones [2] both are important
subunits occurring in a variety of biologically active natural
products. (-)-Botryolide E (1; Fig. 1), an unsaturated -lactone,
was isolated from cultures of the fungicolous Botryotrichum sp.
(NRRL 38180) by Gloer and coworkers in 2008 [3], and it
exhibited promising antibacterial activity against Bacillus subtilis
(MTCC 441), Staphylococcus aureus (MTCC 96) and
Escherichia coli (MTCC 443), as well as antifungal activity
against Aspergillus niger (MTCC 1344) and Saccharomyces
cerevisiae (MTCC 171) [4]. Another class of natural products,
ophiocerins A–C (2-4), which represent
a new type of
tetrahydropyran derivatives with two hydroxyl groups, were
isolated from cultures of the aquatic fungus Ophioceras
venezuelenser [5].
Fig. 1. (-)-Botryolide E and ophiocerins A–C.
Due to the promise of biological activities associated with
natural product containing -lactone or tetrahydropyran moiety,
botryolide E and ophiocerins A–C attracted considerable interest
from synthetic chemists. Venkateswarlu group reported their first
[4] and second generation [6] synthesis of (-)-botryolide-E
featuring Jacobsen’s hydrolytic kinetic resolution of propylene
oxide and Sharpless asymmetric dihydroxylation. A chiral-pool
synthesis of (-)-1 starting from (+)-diethyl (L)-tartrate was
achieved by Madabhushi et al [7]. Das and coworkers developed
another approach to (-)-1 via allyl boration, Sharpless
asymmetric dihydroxylation and ring-closing metathesis reaction
[8]. Likewise, several syntheses of ophiocerins A–C using chiral-
pool sources and asymmetric reactions also have been reported.
Yadav and coworkers accomplish the synthesis of ophiocerins B
———
and C from a chiral epoxide [9] and the synthesis of ophiocerin
C from L-(+)-tartaric acid [10] successively. Kang et al.
synthesized ophiocerins A–C starting from methyl α-D-
glucopyranoside [11] and (R)-(-)-4-penten-2-ol [12] respectively.
Moreover, the Kumar [13], Damera [14] and Das groups [15]
developed other synthetic routes to compounds 2–4 from (R)-
propylene oxide or L-malic acid, independently. Up to now, only
two divergent routes that led to botryolide E and ophiocerins via
a common intermediate were developed in view of the similar
triol moiety of the two type of compounds. Yadav group
employed a chiral homoallylic alcohol to prepare a key
polyhydroxy intermediate in 8 steps, which could be converted
separately to botryolide E and ophiocerin C in 5 steps [16].
 Corresponding author.
E-mail: chenxc@scu.edu.cn

2
Tetrahedron Letters
followed by Wittig olefination were unsuccessful, and the
Kumar group synthesized compounds 1-4 from known D-
unsaturated ester 9 was obtained in very poor yield (0-13% yield).
Thus, the primary alcohol in 5 was masked with TBSCl first, and
acetylation of secondary alcohol 10 using Ac2O gave acetate 11.
Removal of the TBS protecting group in 11 released the primary
glyceraldehyde acetonide in 16 to 19 steps via a common tetraol
intermediate [17].
Scheme 1. Our retrosynthetic analysis of 1-4.
Recently the first synthesis of (+)-botryolide E and its C-7
epimer was achieved from D-glucono--lactone in our laboratory
[18]. In continuation of our interest in the synthesis of bioactive
natural products and their enantiomers using commercial
carbohydrates [9,19], herein we reported a new approach to (-)-
botryolide E and ophiocerins A–C by way of a common building
block derived from D-glucono--lactone.
alcohol 12. Oxidation of alcohol 12 with Dess-Martin
periodinane afforded the corresponding aldehyde 13, without
further purification, which underwent Wittig olefination with
(ethoxycarbonylmethylene)triphenylphosphorane to generate Z-
conjugated ester 14 with good geometric selectivity. Finally, 14
underwent one-pot acetonide deprotection and lactonization in
80% AcOH affording (-)-botryolide-E [23].
Scheme 2. Reagents and conditions: (a) I2, PPh3, imidazole, THF, rt;
(b) LiAlH4, THF, 0oC, 62% over two steps
2. Results and discussion
Our approach to the synthesis of 1-4 was shown in Scheme 1.
It is envisaged that the target molecules 1 and 2-4 could be
prepared from the common intermediate 5 via lactonization or
SN2 cyclization, respectively. (2S,3S,5R)-hexane-1,2,3,5-tetraol 5
was proposed to be derived from D-glucono--lactone (6) by the
successively selective deoxygenation.
Our synthesis began with the preparation of the known ester 7
from 6 (Scheme 2). Following to the literature procedure [20], 6
was converted into the hydroxyl ester 7 in a four-step sequence
involving protection as isopropylidene derivative, Barton-
McCombie deoxygenation [21] and selective hydrolysis of
terminal acetonide. Under the Appel reaction conditions [22], the
primary alcohol group in diol 7 was selectively iodinated leading
to the corresponding iodide 8, in which the simultaneous
reduction of the ester and the iodo functional groups with
excessive LiAlH4 to afford the target common intermediate 5 in
62% overall yield for two steps.
Scheme 3. Reagents and conditions: a) TBSCl, imidazole, CH2Cl2,
0oC, 92%; b) Ac2O, Et3N, DMAP, rt, 92%; c) TBAF, THF, 0oC,
96%; d) Dess−Martin periodinane, CH2Cl2, rt; e) Ph3P=CHCO2Et,
MeOH, 0oC, 72% over two steps; f) 80% aq. AcOH, rt, 91%.
Next, advancing the intermediate 5 toward synthesis of
ophiocerins A–C was set out. Following to Kumar’s strategy
[13,17], 5 was smoothly converted (+)-ophiocerin C (4) via
sequential tosylation of the primary alcohol, base-induced
cyclization and deprotection of acetonide. In Kumar’s work [17],
ophiocerins A–C were synthesized from their common
With the key intermediate 5 in hand, we first aimed the
synthesis of (-)-botryolide E (Scheme 3). The attempts on direct
selective oxidation of the primary hydroxy group in diol 5
intermediate by employing
three different approaches

3
independently. We investigated the direct transformation of 4 to
2 and 3 for the first time. (+)-Ophiocerin C was subjected to
Mitsunobu reaction procedure [24] (1.6eq. DIAD, Ph3P and
BzOH) at room temperature to yield a single monobenzoate 15.
Unfortunately, the Mitsunobu product 15 is difficult to purify due
to the presence of the inseparable impurities derived from DIAD
and Ph3P. However, the impure benzoate 15 was hydrolyzed to
furnish (-)-ophiocerin A in 78% overall yield for two steps after
chromatography purification. It is assumed that the phosphonium
intermediate preferentially binds to the C-4 alcohol oxygen in 4
so that the carboxylate approaches the alkoxy phosphonium salt
from the side opposite to the C-6 methyl group to generate
thermodynamically more stable product 15. Subsequent inversion
of the C-3 hydroxyl configuration in 15 via the second
Mitsunobu reaction was examined. The reaction of the crude 15
with 2.0 eq. DIAD, Ph3P and BzOH proceeded sluggishly at
50oC, and considerable 15 was remained after a long span. The
resulting mixture containing 15 and 16 was treated with K2CO3 in
methanol to afford 2 (45% for 3 steps) and 3 (22% for 3 steps),
Acknowledgments
This work was supported by grants from the National Natural
Science Foundation of China (No. 21172153), the Sichuan
Science and Technology Program (2019YJ0032) and “the
Fundamental Research Funds for the Central Universities”. We
thank the Comprehensive Training Platform of Specialized
Laboratory, College of Chemistry, Sichuan University, for
spectral data measurement.
Supplementary Material
Supplementary
data
(experimental
procedures
and
C
characterization data for compounds, and copies of H and 13
1
NMR spectra for compounds 5, 10, 11, 12, 14, (-)-1, (-)-2, (-)-3,
(+)-4 associated with this article can be found, in the online
version, at
Scheme 4. Reagents and conditions: (a) TsCl, NaH, THF, 0oC; (b) tBuOK, Et2O, 0oC; (c) pTsOH, MeOH,
rt, 80% over three steps; (d) DIAD, Ph3P, BzOH, THF, rt; (e) K2CO3, MeOH, rt, 78% over 2 steps; (f)
DIAD, Ph3P, BzOH, THF, 50oC; (g) DIAD, Ph3P, BzOH, toluene, 110oC; (h) K2CO3, MeOH, rt, 45% for 2
and 22% for 3 over three steps (d, f, h), 33% for 2 and 41% for 3 over two steps (g, h).
which was readily separated on column chromatography. In order
References and notes
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lactone compound (-)-botryolide
E
and tetrahydropyran
derivative ophiocerins A-C in 3 to 6 steps. Moreover, the
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Mitsunobu reaction was investigated for the first time. We think
that this strategy should be employable for more related
unsaturated lactone and hydroxylated pyran derivatives.

4
Tetrahedron Letters
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1
νmax: 3450, 2982, 2930, 1740, 1376, 1247, 1036, 827cm-1. H NMR
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2.0 Hz, 1H), 5.13 (m, 1H), 5.01 (dt, J = 4.0, 1.6 Hz, 1H), 3.86 (dt, J =
8.3, 4.4 Hz, 1H), 2.83 (s, 1H), 2.05 (s, 3H), 1.76 – 1.59 (m, 2H), 1.26
(d, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.9, 171.8,
153.8, 122.8, 85.5, 67.7, 67.3, 39.2, 21.3, 20.7. HRMS (ESI-TOF):
167；
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+
m/z [M+Na]+ C10H14NaO5 : 237.0733, found: 237.0736.
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CH2Cl2); IR (neat) νmax: 3280, 1451, 1378, 1240, 1147, 1091, 1073,
1
1023 cm-1; H NMR (400 MHz, CDCl3) δ 4.32 (s, 2H), 3.90 (dd, J =
11.2, 5.0 Hz, 1H), 3.55 – 3.45 (m, 2H), 3.42(ddd, J = 10.0, 9.0, 5.2
Hz, 1H ), 3.10 (dd, J = 11.0, 10.2 Hz, 1H), 1.94 (ddd, J = 13.2, 4.8,
1.6 Hz, 1H), 1.30 (m,1H), 1.18 (d, J = 6.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 73.0, 72.8, 72.0, 69.7, 40.6, 21.2. HRMS (ESI-TOF):
m/z [M+Na]+ calcd for C6H12NaO3+ 155.0679; found 155.0685.
(b) Y. Zhang, X. Liu, F. Shui, F. Zhou, J. Cui, X. ChenTetrahedron .
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(-)-2: mp 62-64 °C; [ α]D25 = –25.7 (c =1.0, CH2Cl2); IR (neat) νmax
=
3390, 1381, 1095, 1054, 1011 cm–1. H NMR (400 MHz, CDCl3) δ
4.06 (m, 1H), 3.80 (ddq, J = 12.6, 6.3, 2.1 Hz, 1H), 3.74 – 3.63 (m,
2H), 3.54 (m, 1H), 2.78 (s, 2H), 1.91 – 1.81 (ddd, J = 14.3, 3.6, 2.3
Hz, 1H), 1.51 (ddd, J = 14.0, 11.2, 2.6 Hz, 1H), 1.14 (d, J = 6.3 Hz,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 67.3, 67.2, 67.0, 65.9, 39.0,
20.8 ppm. HRMS (ESI-TOF): m/z [M+Na]+ calcd for C6H12NaO3+
155.0679; found 155.0683.
1
(-)-3: [α]D25 = –35.7 (c = 0.3, CH2Cl2); IR (neat) νmax = 3388, 1452,
1380, 1266, 1079, 1004 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.95
(dd, J = 1.6, 12.3, Hz, 1H), 3.95(m, 1H), 3.85 (m, 1H), 3.71 (m, 1H),
3.48 (m, 1H), 2.53 (s, 1H), 2.01 (s, 1H), 1.80 (ddd, J = 14.1, 10.8, 3.1
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C
NMR (100 MHz, CDCl3): δ 68.4, 68.3, 67.5, 67.3, 36.0, 21.2. HRMS
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+
(ESI-TOF): m/z [M+Na]+ calcd for C6H12NaO3 155.0679; found
155.0678.
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(1977) 1718-1723;

5
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template box below.
Graphical Abstract
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Synthesis of botryolide E, ophiocerins A, B
Leave this area blank for abstract info.
and C from D-glucono--lactone
Faling Zhou, Xiaojing Liu, Yuanliang Jia, Yue Hu, Guiyin Luo and Xiaochuan Chen*
Highlights
 The first employment of D-glucono--
lactone to synthesize (-)-Botryolide E
and ophiocerins A–C
 Concise and versatile synthetic route
 The first transformation of ophiocerin C
to ophiocerins A and B via Mitsunobu
reaction