Total Synthesis and Stereochemical Revision of 4,8-Dihydroxy-3,4-dihydrovernoniyne

Article abstract of DOI:10.1021/acs.orglett.7b01620

The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot-Chodkiewicz coupling and

Full text of DOI:10.1021/acs.orglett.7b01620

Letter
pubs.acs.org/OrgLett
Total Synthesis and Stereochemical Revision of 4,8-Dihydroxy-3,4-
dihydrovernoniyne
Suresh Kanikarapu,† Kanakaraju Marumudi,‡ Ajit C. Kunwar,‡ Jhillu S. Yadav,†
and Debendra K. Mohapatra*,†
‡
†Natural Products Chemistry Division and Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5
and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot−
Chodkiewicz coupling and Sonogashira cross-coupling of terminal acetylenes. Detailed comparison of the 1H and 13C NMR data
and specific rotation with that of the natural product led to the revision of the absolute stereochemistry of the natural product as
(4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.
The retrosynthetic route for the synthesis of (4S,5R)-4,8-
dihydroxy-3,4-dihydrovernoniyne 5 is illustrated in Scheme 1.
We envisioned a convergent strategy based on the coupling of
functionalized alkyne in 9 and bromodiyne 10 either by a
Cadiot−Chodkiewicz7 cross-coupling reaction or by Sonoga-
shira8 coupling reaction. The functionalized alkyne in 9 could
be synthesized from homopropargyl alcohol 12 using Jin’s one-
step dihydroxylation−oxidation protocol,9 which in turn could
be accessible from commercially available D-mannitol 14.
Similarly, the bromodiyne 10 can be obtained from readily
available propargyl alcohol 15.
Thus, the synthesis began with the preparation of
bromodiyne 10 and diyne 11, which were easily prepared
from commercially available propargyl alcohol 15 (Scheme 2).
Conversion of the propargyl alcohol 15 to the PMB ether
following a mild one-step heterogeneous protocol10 and further
reaction with NBS and AgNO3 afforded bromoacetylene 1311
in 97% yield. Coupling of bromoalkyne 13 with TMS-acetylene
under Cadiot−Chodkiewicz conditions7 provided the cross-
coupling product 17 (62%) along with the dimer resulting from
the homocoupling in 23% yield. Formation of the dimer
resulting from the TMS-acetylene was investigated by perform-
ing the coupling reaction. Interestingly, under Sonogashira
conditions (Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF)8 (Table 1,
atural products bearing a polyacetylenic group with
Nvaried and diverse substitutions are unique structural
motifs displaying several bioactivity profiles.1 Among them,
unsymmetrical 1,3-diynes have received considerable attention.
Over 1000 polyacetylenic natural products have been isolated
to date from organisms such as plants, mosses and lichens,
fungi, bacteria, insects, algae, sponges, and tunicates.2 These
natural products are relatively unstable and reactive due to their
potential to undergo oxidative, photolytic, or pH-dependent
decomposition.3 Their unique rodlike structure and often
conjugated character is responsible for the cytotoxic, anti-
bacterial, antiparasitic, insecticidal, antitumor, anti-inflamma-
tory, antiviral, and phytotoxic activities.4
Recently, Biavatti and co-workers5 isolated eight polyacety-
lene-containing butyrolactone natural products 1−8, seven of
which are new, from the leaves of Vernonia scorpioides
(Asteraceae) (Figure 1). This herb is used in folk medicine
for the treatment of several skin diseases, such as allergies, skin
parasites, irritation, chronic skin injuries (ulcers), and itching.
Their structures were established by 1D and 2D NMR
spectroscopy and MS analysis.
We recently accomplished the total synthesis of the diyne-
containing natural product ivorenolide A.6 In continuation of
our efforts, we report herein the first asymmetric total synthesis
of (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne and revision
of its absolute stereochemistry based on the synthesis.
Received: June 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
a
entry
cross-coupling conditions
17 (%)
1
2
CuCl, NH2OH·HCl, n-BuNH2, ether, 0 °C, 30 min
CuI, (Ph3P)2PdCl2, DIPA, THF, 0 °C, 1 h
62
85
a
Isolated yield.
in quantitative yield.12 Reaction of compound 17 with K2CO3
in MeOH furnished the diyne 11 in 96% yield (Scheme 2).
Synthesis of the lactone 9 commenced from a known
homoallylic alcohol 18, which was synthesized from D-mannitol
following a procedure described in the literature.13 Modified
Mosher’s ester method14 was applied to assign the stereocenter
at C4 bearing the secondary hydroxyl group, and the center was
found to have an S configuration. The secondary alcohol group
present in 18 was protected as its MOM-ether 19 in good yield.
Compound 19 was treated with 1 M HCl in acetonitrile to
obtain the diol 20 in 92% yield. Treatment of the diol 20 with
trisylimidazole in the presence of NaH in THF furnished the
epoxide 21. Regioselective opening of the epoxide ring using
the Yamaguchi−Hirao alkynylation protocol15 afforded the β-
hydroxy alkyne 22 in 85% yield. At this stage, the absolute
stereochemistry at C5 was determined as R based on a modified
Mosher’s ester method. Removal of the TMS group under
anhydrous K2CO3 in MeOH conditions furnished the
homopropargyl alcohol 12 in quantitative yield. The terminal
double bond was selectively oxidized following Jin’s one-step
dihydroxylation−oxidation protocol9 to obtain the desired
lactol 23 in 82% yield. The lactol 23 was oxidized with PCC in
CH2Cl2 to afford lactone 9 in 90% yield. The alkyne group was
converted to bromoalkyne 24 by using NBS and a catalytic
amount of AgNO3 in 97% yield (Scheme 3).11
Figure 1. Structures of polyacetylenes 1−8.
Scheme 1. Retrosynthetic Analysis
With the requisite fragments in hand, coupling of the alkyne
9 with bromodiyne 10 was investigated under Cadiot−
Scheme 3. Synthesis of the Alkyne Fragment 9 and
Bromoalkyne Fragment 24
Scheme 2. Synthesis of Bromodiyne 10 and Diyne 11
entry 2), the required cross-coupling product 17 was obtained
in 85% yield along with homocoupled dimer in 5% yield were
obtained. Upon treatment with NBS and AgNO3, compound
17 underwent in situ deprotection of the C-silyl group followed
by bromination of the terminal alkyne to obtain bromodiyne 10
B
DOI: 10.1021/acs.orglett.7b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chodkiewicz reaction conditions. While performing the
reaction in diethyl ether was futile (Table 2, entry 1), the
Scheme 5. Synthesis of (4S,5S)-4,8-Dihydroxy-3,4-
dihydrovernoniyne 5a
Table 2. Optimization of the Reaction Conditions for
Cadiot−Chodkiewicz and Sonogashira Cross-Coupling
yield
(%)
entry R1
R2
cross-coupling conditions
1
2
3
4
5
H
H
H
Br
Br
Br CuCl, NH2OH·HCl, n-BuNH2, Et2O, 0 °C
Br CuCl, NH2OH·HCl, n-BuNH2, CH2Cl2, 0 °C
Br CuI, (Ph3P)2PdCl2, DIPA, THF, rt
0
60
75
55
90
H
H
CuI, (Ph3P)2PdCl2, DIPA, THF, rt
CuCl, NH2OH·HCl, n-BuNH2, CH2Cl2, 0 °C
reaction in dichloromethane afforded the product in 60% yield
(Table 2, entry 2). Performing the reaction under Sonogashira
conditions furnished the product in 75% yield. Interestingly,
reaction of the bromoalkyne 24 (derived from 9) with the
diyne 11 gave the required product 25 in 90% yield (Table 2,
entry 5) (Scheme 4). These reactions are summarized in Table
2.
Table 3. Comparison of 13C NMR of Natural Product with
Synthetic 5 and 5a in Acetone-d6 (400 MHz)
Scheme 4. Synthesis of (4S,5R)-4,8-Dihydroxy-3,4-
dihydrovernoniyne 5
The PMB group in compound 25 was selectively deprotected
with DDQ under standard reaction conditions to furnish the
primary alcohol 26 in 92% yield. Deprotection of the MOM
ether in 26 with BF3·OEt2 in dimethyl sulfide at −40 °C
provided (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 in
70% yield.16 The specific rotation of the synthetic sample had
experiments in two different solvents, acetone-d6 and
acetonitrile-d3. The presence of medium range characteristic
NOE correlations: H3a/4-OH, H4/(H1′a-H1′b) and 4-OH/
H5 in 5 supported an “R” configuration at C5 whereas H3a/4-
OH and 4-OH/(H1′a-H1′b) in 5a are consistent with the
configuration at C5 to be “S”.
25
opposite sign [[α]D +4.61 (c 0.76, EtOH)] compared to that
reported for the natural product [lit.5 [α]D −2.16 (c 0.74,
25
1
EtOH)]. Moreover, the H and 13C NMR spectral data of
The specific rotation of (4S,5S)-5a showed [[α]D25 −61.5 (c
0.94, EtOH)], however, did not match in magnitude with the
value that reported for the natural product [lit.5 [α]D25 −2.16 (c
0.74, EtOH)], a plausible reason for the discrepancy is either an
impure sample of the natural products or the unstable nature of
the polyene compounds, which is reflected in the NMR spectra
of the natural product.5 Therefore, the results led to the
revision of the configuration at C-5 to be “S”.
synthetic 5 were not in agreement with those reported (see the
Supporting Information). As both the spectral data and sign of
optical rotation for synthetic sample were not matched with
those reported for the natural product, we surmised that the
isolated compound might be diastereomer of 5. Therefore, we
undertook the total synthesis of the other diastereomer of 5
(i.e., 5a) by following a route similar to that described (Scheme
5 and Supporting Information for further details). Gratifyingly,
compound 5a displayed 1H and 13C NMR spectral data
identical to those reported for the natural product (4S,5R)-4,8-
dihydroxy-3,4-dihydrovernoniyne 5 (Table 3). The structures
of 5 and 5a were further confirmed by detailed 2D NMR
In summary, first stereoselective total synthesis of two
isomers of 4,8-dihydroxy-3,4-dihydrovernoniyne 5 and 5a was
accomplished in 11 steps with 28% overall yield starting from
known intermediate 18. The salient features of this synthesis
include Cadiot−Chodkiewicz coupling, Pd-catalyzed cross-
C
DOI: 10.1021/acs.orglett.7b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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1
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(5) Pollo, L. A. E.; Bosi, C. F.; Leite, A. S.; Rigotto, C.; Kratz, J.;
spectral data of the synthetic 5 and 5a were compared with
those reported for the natural product. On the basis of the data,
stereostructure of the natural product was reassigned to
(4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.
Simoes, C. M. O.; Fonseca, D. E. P.; Coimbra, D.; Caramori, G.;
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ASSOCIATED CONTENT
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01620.
Experimental procedure and characterization of new
compounds (1H, 13C NMR spectra, 2D-NMR spectra)
(PDF)
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Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York,
AUTHOR INFORMATION
2002; p 493. (c)
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■
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Corresponding Author
*E-mail: mohapatra@iict.res.in.
ORCID
(9) Yu, Y.; Mei, W.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217−3219.
Debendra K. Mohapatra: 0000-0002-9515-826X
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Council of Scientific and Industrial research
(CSIR), New Delhi, India, for financial support as part of the
XII Five Year Plan Programme under the title ORIGIN (CSC-
0108). S.K. and K.M. thank CSIR, and UGC, New Delhi, India,
for financial assistance in the form of fellowships.
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Org. Lett. XXXX, XXX, XXX−XXX