Total synthesis of the proposed structure of xylarolide

Article abstract of DOI:10.1016/j.tetlet.2019.150944

A total synthesis of a proposed structure of xylarolide is described. The key features of the synthesis include Sharpless asymmetric reaction, Wittig olefination, Sharpless asymmetric dihydroxylation, Still-Gennari olefination and Yamaguchi lactonization. The differences in the spectroscopic data of the synthetic and natural product indicate a revision of the assigned structure.

Full text of DOI:10.1016/j.tetlet.2019.150944

Accepted Manuscript
Total synthesis of the proposed structure of Xylarolide
Mopuri Sudhakar Reddy, Palakodety Radha Krishna
PII:
S0040-4039(19)30694-X
https://doi.org/10.1016/j.tetlet.2019.150944
150944
DOI:
Article Number:
Reference:
TETL 150944
Tetrahedron Letters
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Revised Date:
Accepted Date:
17 June 2019
10 July 2019
16 July 2019
Please cite this article as: Sudhakar Reddy, M., Radha Krishna, P., Total synthesis of the proposed structure of
Xylarolide, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.150944
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Graphical Abstract
Total synthesis of the proposed structure of Xylarolide Leave this area blank for abstract info.
Mopuri Sudhakar Reddy and Palakodety Radha Krishna*
Sharpless asymmetric dihydroxylation
Wittig olefination
OH
HO
Still-Gennari olefination
O
Sharpless assymetric
epoxidation
O
Yamaguchi lactonization

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Total synthesis of the proposed structure of Xylarolide
Mopuri Sudhakar Reddya,b and Palakodety Radha Krishnaa*
aOrganic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110025, India.
Email: prkgenius@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A total synthesis of a proposed structure of Xylarolide is described. The key features of the
synthesis include Sharpless asymmetric reaction, Wittig olefination, Sharpless asymmetric
dihydroxylation, Still-Gennari olefination and Yamaguchi lactonization. The differences in the
spectroscopic data of the synthetic and natural product indicate a revision of the assigned
structure.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Xylarolide,
Sharpless asymmetric reaction,
Still-Gennari olefination,
Yamaguchi lactonization.
Many naturally occurring 10-membered ring containing
lactones (decanolides) are the most abundant and they also show
a broad spectrum of bioactivities such as antifungal, antibacterial,
antimalarial and anticancer properties.1 Fungi of the genus
Xylaria are a rich source of bioactive metabolites, thus they have
attracted much attention of chemists and biologists. A novel 10-
membered nonenolide, xylarolide (1) (fig. 1) was isolated from
the fungal strain named 101 from Gaoligong Mountain of
southwestern China, and identified it as Xylaria sp. by Yue-Mao
Shen et al.2 and found to exhibit good activity. Thus, due to the
fascinating biological properties and structural diversities of 10-
membered macrolides, considerable interest was generated in the
synthetic community and encouraged us to take up its synthesis.
In continuation with our interest in the synthesis of 10-membered
hydroxylated macrolides,3 we next describe a stereoselective
approach to the total synthesis of xylarolide.2
required seco-acid precursor 2 could be obtained from 3 by
sequential oxidation, Wittig olefination, Still-Gennari olefination
followed by ester hydrolysis and PMB deprotection. Compound
3 could be generated from 4 by asymmetric dihyroxylation,
acetonide protection and ester reduction. Next, the synthesis of
compound 4 in turn could be conceived from the commercially
available (E)-2-hexen-1-ol by suitable functional group
transformations like Sharpless asymmetric epoxidation,
regioselective ring-opening, deprotection and Wittig olefination.
OH
PMBO
O
HO
O
HO
OH
OH
O
O
O
3
O
O
2
1
OPMB
O
O
O
OH
4
5
OH
4
HO
5
6
9
3
2
7
Scheme 1. Retrosynthetic analysis of xylarolide
O
1
8
As outlined in Scheme 1, our synthesis began with known
epoxy alcohol 54, which was readily synthesized from
commercially available (E)-2-hexen-1-ol 6. Regioselective
reductive ring-opening of epoxide 5 with Red-Al afforded a
separable major 1,3 diol5 7 in 82% yield. Diol 7 was protected as
its PMB-acetal under acid conditions (p-TsOH) (94%). Next, the
acetal was regioselectively opened with diisobutylaluminium
hydride (DIBAL-H) to furnish the corresponding primary alcohol
9 in 89%.
10
11
O
1
12
.
Figure 1. Structure of xylarolide (1)
The retrosynthetic strategy (Scheme 1) of 1 reveals that it
could be synthesized by the Yamaguchi lactonization as the
macrocyclization step for the synthesis of xylarolide. The

2
Tetrahedron Letters
9
Yamaguchi conditions8b-c,
(2,4,6-trichlorobenzoyl chloride,
OH
Et3N, DMAP, toluene at 60 °C for 12 h) afforded the decanolide
core 16 in 64% yield. Finally, removal of the acetonide
protecting group in 16 by using 6N HCl afforded the target
compound 1 in 86% yield.
Ref4
O
a
b
OH
OH
OH
.
7
5
6
OCH3
1
However, there were differences found in the H and
OPMB
O
13C NMR spectra of the synthetic and natural product (Table 1).
Therefore, we suggest a structural revision of the proposed
structure.
OPMB
O
O
c
d
e
O
OH
4
9
8
PMBO
OH
O
PMBO
O
O
f
Table 1. 1H and 13C data of natural product and synthetic
compound.
O
O
OH
O
11
10
Scheme 2.
______________________________________________________
a) Red-Al, CH2Cl2, 0 oC-rt, 1 h, 82% b) Anisaldehyde dimethyl acetal, p-TsOH, CH2Cl2, 0
oC-rt, 1 h, 94% c) DIBAL-H, CH2Cl2, 0 oC, 89% d) i) DMP, CH2Cl2, 0 oC-rt, 1 h ii) Ph3P=CHCO2Et,
C6H6,reflux, 81% e) AD-mix-, tBuOH:H2O, 0 oC, 8 h, 90% f) 2,2-DMP, CH2Cl2, p-TsOH, 0 oC-rt , 3
h, 91%.
Position
Natural product
Synthetic product (1)
δ 13C NMR 1H NMR
δ 13C NMR 1H NMR
1
2
3
4
5
6
7
8
168.2
126.1
139.2
130.2
167.4
Furthermore, oxidation of alcohol 9 (Scheme 2) with Dess-
6.42(d, J=11.7)
6.72(d, J=11.7)
6.26 (d, J=15.2)
127.6
137.7 6.73(dd, J=5.3,11.7)
131.4 6.42(d, J=11.7)
6.46(m)
Martin periodinane (DMP) in CH2Cl2 at 0 °C gave the
corresponding aldehyde, which was immediately subjected to
two-carbon Wittig olefination6 (Ph3P=CHCO2Et/C6H6/reflux) to
afford α,β-unsaturated ester 4 as a separable major E-isomer (9:1,
81% over two steps). Dihydroxylation of 4 under the Sharpless
asymmetric dihydroxylation conditions7 (AD mix α) afforded
α,β-dihydroxy ester 10 in 90%. The dihydroxy ester 10 was
converted into acetonide ester 11 by using 2,2-DMP, CH2Cl2, p-
TsOH, in 91% yield.
133.4 5.48(dd, J=10.1,15.2) 134.5 6.39(dd, J=10.2,15.7)
78.5
76.7
40.0
3.90(t, J=9.1)
3.53 (t, J=7.7)
1.87-1.89(m)
70.0
68.9
39.7
4.25(t, J=8.5)
3.99(t, J=7.7)
1.80-1.75(m)
1.66-1.63(m)
4.51(m)
1.60-1.55(m)
1.26-1.25(m)
0.93(t, J=7.1)
9
75.5
38.7
18.5
13.9
4.91 (m)
1.42-1.5(m)
1.35(m)
68.3
38.8
18.8
14.0
10
11
12
Subsequently, reduction of acetonide ester 11, with DIBAL-H
provided alcohol 3 in 92% yield (Scheme 3). Oxidation of the
alcohol 3 with DMP in CH2Cl2 at 0 °C gave corresponding
aldehyde, which was subjected to Wittig olefination6
(Ph3P=CHCO2Et/C6H6) under reflux conditions to afford
compound 12 (81%). Further, reduction of the ester group in 12
with DIBAL-H afforded the allyl alcohol 13 in 83% yield.
Oxidation of alcohol 13 with DMP in CH2Cl2 at 0 °C gave the
corresponding aldehyde, which was directly subjected to a Still-
Gennari reaction8 with methyl [bis(2,2,2)-trifluoroethoxy]
phosphonoacetate in THF at -78 °C for 1h to afford the
chromatographically separable α,β-unsaturated ester 14 as the
major Z-isomer (Z/E = 92:8) in 74% yield. Base hydrolysis of
ester 14 with LiOH in THF/H2O afforded the corresponding acid
15 in 90% yield.
0.93(t, J=7.3)
In summary, we accomplished the linear, stereocontrolled
total synthesis of Xylarolide.1,10 The key features of the synthesis
include Sharpless asymmetric reaction, Wittig olefination,
Sharpless asymmetric dihydroxylation, Still-Gennari olifination
and Yamaguchi lactonization. The differences in the spectral data
between synthetic 1 and natural product strongly suggested a
structural misassignment during the isolation of xylarolide and a
structural revision is thus warranted.
Acknowledgements
One of the authors (M.S.R) is thankful to the CSIR, New
Delhi for financial support in the form of fellowship.
IICT/Pubs./2019/206.
PMBO
O
PMBO
O
O
b
a
c
References
11
OH
O
O
O
3
12
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PMBO
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d
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OH
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O
OH
O
h
O
O
O
O
16
Scheme 3.
1
a) DIBAL-H, CH2Cl2, 0 oC, 92%; b) i) DMP, CH2Cl2, 0 oC-rt, 1 h; ii) Ph3P=CHCO2Et,
C6H6,reflux, 81% h; c) DIBAL-H, CH2Cl2, h; ii)
oC, 83%; d) i) DMP, CH2Cl2, oC-rt,
6
0
0
1
MeO2CCH2P(O)(OCH2CF3)2, NaH, THF, –78 °C,1 h, 74%; e) LiOH.H2O, THF:H2O, (3:1:) 8 h, 90%; f)
DDQ, CH2Cl2/H2O (19:1) 0 oC-rt, 1 h, 89% g) 2,4,6-trichlorobenzoylchloride DIPEA, DMAP, toluene,60
oC, 64%, 24 h; h) 6N HCl, THF, 0 oC, 86%, 1 h.
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in 15 was deprotected by using DDQ in CH2Cl2/H2O (9:1) to
provide seco-acid 2 in 89% yield. Next, seco-acid 2 under

3
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10. For spectral data and experimental procedures, please see
Supporting Information

4
Tetrahedron Letters
Highlights
1. Xylarolide synthesis
2. 10-Membered macrolide
3. 3 Stereocenters and 2 olefinic bonds
11.