Total Synthesis of Pestalotioprolide e and Structural Revision of Pestalotioprolide F

Article abstract of DOI:10.1021/acs.orglett.8b01894

A short and convergent strategy for the first asymmetric total synthesis of cytotoxic macrolides pestalotioprolides E and F has been developed. The key features of this synthesis include Takai olefination, Sonogashira coupling, Ni-assisted partial hydroge

Full text of DOI:10.1021/acs.orglett.8b01894

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of Pestalotioprolide E and Structural Revision of
Pestalotioprolide F
Debobrata Paul, Sanu Saha, and Rajib Kumar Goswami*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
*
S Supporting Information
ABSTRACT: A short and convergent strategy for the first
asymmetric total synthesis of cytotoxic macrolides pestalotio-
prolides E and F has been developed. The key features of this
synthesis include Takai olefination, Sonogashira coupling, Ni-
assisted partial hydrogenation of alkyne, modified Steglich
reaction to generate the ester moiety, and intramolecular
Horner−Wadsworth−Emmons (HWE) olefination to com-
plete the macrocycle. This synthetic study revised the
proposed structure of pesralotioprolide F.
aturally evolved 14-membered macrolides drew substan-
tial attention of the scientific community due to their
pestalotioprolides E and F consist of three stereogenic centers
among which two are hydroxylated, a conjugated diene with E,Z-
geometry and an E-olefin conjugated with the lactone carbonyl.
The installation of a conjugated diene (C −C ) and an olefin
N
broad structural variations and diverse range of biological
1
activities. Liu and Proksch et al., in 2016, had discovered a new
5
8
series of 14-membered macrolides, pestalotioprolides B−H (1−
, Figure 1), from an endophytic fungi Pestalotiopsis microspora
(C −C ) separated by a hydroxylated center in a 14-membered
2
3
7
macrocycle is unprecedented and hence provides a formidable
challenge. We report herein a convergent and flexible common
route for the first total synthesis of the target molecules that
revised the putative structure of pestalotioprolide F.
The retrosynthetic analysis of pestalotioprolides E (4) and F
(
5) is depicted in Scheme 1. The use of intramolecular HWE
5
reaction in 14-membered ring formation is rare. We adopted
this strategy as the key step for macrocyclization to make our
synthesis more convergent. Pestalotioprolide E (4) would be
realized therefore from the suitable HWE precursor 8a, whereas
pestalotioprolide F (5) would be accessed from another HWE
precursor, 8b. Both precursors 8a and 8b could be constructed
Scheme 1. Retrosynthetic Analysis of Pestalotioprolides E
(
4) and F (5)
Figure 1. Chemical structures of pestalotioprolides (B−H) (1−7).
isolated from fresh fruits of the mangrove plant Drepanocarpus
2
lunatus. Many of these members are reported to exhibit good to
2
moderate in vitro anticancer activities. Attractive architectural
features, good bioactivities, and natural scarcity made them
3
promising targets for chemical synthesis. In continuation of our
4
ongoing program on the synthesis of bioactive natural products,
4a
especially on the pestalotioprolide family of macrolides, we
envisaged the total synthesis of pestalotioprolides E and F to get
these materials in sufficient quantities to allow further biological
studies. Pestalotioprolides E and F exhibited cytotoxicities to
murine lymphoma cell line (L5178Y) with IC50 values of 3.4,
and 3.9 μM, respectively, while pestalotioprolide E showed
promising activity against human ovarian cancer cell line
Received: June 18, 2018
2
(
A2780) with an IC50 value of 1.2 μM. Structurally,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Key Segments (9, 10, ent-10) of Pestalotioprolides E and F
separately from the common intermediate 9 and alcohol 10 or
Scheme 3. Completion of Total Synthesis of
Pestalotioprolide E (4) and Putative Structure of
Pestalotioprolide F (5)
4b,6
alcohol ent-10, respectively, using Sonogashira coupling
as
one of the pivotal steps.
The synthesis of key segments 9, 10, and ent-10 of
pestalotioprolides E and F is delineated in Scheme 2. The
7
known compound 11, prepared from commercially available
7
(
S)-(−) propylene oxide, was treated with TBAF to deprotect
the TBS ether and then subjected to react with TESCl/Et N/
3
DMAP to get the corresponding TES ether, which subsequently
n
4c,8
was treated with Me SI/ BuLi to obtain compound 12. Next,
3
compound 12 was transmuted to compound 13 using TBSOTf/
2
,6-lutidine. Compound 13 was then dihydroxylated using
OsO /NMO and subsequently treated with NaIO /NaHCO to
4
4
3
produce the corresponding aldehyde, which was finally
4c,9
subjected to Takai olefination
to produce alcohol 14 in
complete E-selectivity with in situ deprotection of TES ether.
1
0
Alcohol 14 was then esterified with the known phophonate 15
4d,11
using the modified Steglich condition
in 86% yield. However, the known compound 17, prepared
from commercially available epoxide 16 following a literature
to achieve compound
12
9
1
2
procedure, was subjected to oxidative cleavage using OsO4/
NMO followed by NaIO /NaHCO . The resultant aldehyde
was then exposed to Corey−Fuch reaction using CBr /Ph P/
Et N followed by BuLi treatment to yield the corresponding
4
3
13
4
3
n
3
alkyne intermediate, which finally was reacted with Li-
naphthalenide to achieve compound 10 in 57% overall yield
(
over four steps). Following similar chemistry, commercially
available epoxide ent-16 was transformed to the required
compound ent-10 via the known intermediate ent-17 with good
overall yield.
Table 1. Optimization of Intramolecular HWE Cyclization
time
The completion of total synthesis of the reported structure of
pestalotioprolides E and F is described in Scheme 3. Compound
entry
conditions
NaH, THF, 0 °C−rt
(h)
yield (%)
4b,6
1
2
3
4
1
10−15
no reaction
30
9
was separately subjected to Sonogashira coupling
with
KHMDS, THF, 0 °C−rt
12
2
compounds 10 and ent-10 to obtain compounds 18a and 18b,
respectively. Both compounds 18a and 18b were subjected
Ba(OH) ·8H O, THF/H O (40:1), 0 °C−rt
2
2
2
1
4
DIPEA, LiCl, CH CN, 0 °C−rt
3
26
3
separately to partial hydrogenation using Ni(OAc) ·4H O/
2
2
NaBH /EDA to produce compounds 8a and 8b, respectively.
4
Compound 8a was then oxidized to the corresponding aldehyde
unidentified product in small amount was also found. Both the
silyl ethers of compound 19a were then deprotected using CSA
to achieve compound 4. In a similar way, compound 5 was
synthesized from compound 8b via the intermediate 19b in
and concomitantly was subjected to crucial intramolecular HWE
5
olefination to complete the macrocycle. A number of
conditions (Table 1) have been tested at this stage to optimize
1
13
the HWE reaction for macrocyclization. Ba(OH) ·8H O (entry
good overall yield. The H and C NMR data (NMR
comparisons in Table S1, Supporting Information) and optical
2
2
3
1
) was found to be best compared to others to obtain compound
9a in 30% yield. No dimerized product was detected, but an
2
0
rotation [reported [α]D = +222.0 (c 1.8, MeOH); observed
B
DOI: 10.1021/acs.orglett.8b01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
α]D20 = +218.0 (c 0.1, MeOH)] of the synthesized compound 4
Letter
[
Scheme 4. Completion of Total Synthesis of the Actual
Structure of Pestalotioprolide F and Its Diastereomer
were in good agreement with the data reported for the isolated
2
pestalotioprolide E , which unambiguously confirmed its total
1
synthesis. However, discrepancies in chemical shifts of H and
1
3
C NMR resonances between the synthesized compound 5 and
1
isolated pestalotioprolide F were observed. The H NMR signals
of H-3, H-7, and H-9 protons of the synthesized compound 5
recorded at δ 7.11, 6.40, and 4.04 ppm, respectively, whereas
these resonances for the isolated compound were reported to be
1
at δ 7.03, 6.26, and 3.98 ppm. Moreover, the H NMR splitting
pattern at δ 1.75−0.8 ppm region was quite different from the
reported spectra. The ROESY correlations of synthesized
compound 5 were also differed. The ROESY correlations
between H-2 and H-4 were observed in our case, whereas those
were absent in the reported data of the isolated natural product
(
Figure S1, Supporting Information). Moreover, noticeable
13
mismatches in the C NMR of C-2, C-3, C-11, and C-12 (NMR
comparisons in Table S2, Supporting Information) were also
observed.
The optical rotation value of compound 5 deviated
2
0
considerably from the reported value [reported [α] = +9.0
D
(
c 0.5, MeOH); observed [α]D20 = +64.6 (c 0.34, MeOH)]. This
clearly indicated that isolated pestalotioprolide F might be a
different diastereomer of the proposed structure (5). This led us
to explore the actual structure of pestalotioprolide F.
There are three stereocenters in the molecule that would give
rise to a total of eight isomers. We have initially excluded four
structures 4, ent-4 (enantiomer of compound 4), 5, and ent-5.
Thus, it might be assumed that the actual structure of
pestalotioprolide F would be one among the possible structures
of 20, ent-20, 21, and ent-21 (Figure 2). As the major
hydrogenated to obtain alcohol 24, which was subjected to IBX
4a
oxidation followed by Takai olefination to yield olefin 25 with
complete E-selectivity. Olefin 25 was converted to compounds
2
0 and 21 in good overall yield via the intermediates 26a/26b
and 27a/27b (Scheme 4) following the similar sequence of
reactions as adopted in the synthesis of compounds 4 and 5
1
13
(
Schemes 2 and 3). The H and C NMR data of both the
compounds 20 and 21 were recorded. We were delighted to see
1
13
that both the H and C NMR data of compound 20 matched
perfectly with the reported data of isolated pestalotioprolide F
(
NMR comparisons in Table S3, Supporting Information). The
2
0
optical rotation was also in good agreement [reported [α]
+
=
D
2
0
9.0 (c 0.5, MeOH); observed [α]D = +13.3 (c 0.17, MeOH)].
This result confirmed the total synthesis of the actual structure
Figure 2. Possible structures of isolated pestalotioprolide F.
of isolated pestalotioprolide F. On the contrary, noticeable
1
13
mismatches were observed in H and C NMR data (NMR
comparisons in Table S4, Supporting Information) as well as in
1
mismatches in H NMR were observed for the protons adjacent
2
0
to C-4 and C-9 centers in the synthesized compound 5, we
planned to change the configurations of C-4 and C-9 hydroxy
centers by keeping the configuration of remote C-2 methyl
center unchanged with respect to the proposed structure (5).
Therefore, compounds 20 and 21 were considered as our new
synthetic targets. We started our synthesis from the known
optical rotation value [observed [α]
D
= −64.4 (c 0.47,
MeOH)] between the synthesized compound 21 and the
isolated natural pestalotioprolide F.
In summary, we report the first total synthesis of
pestalotioprolides E and F using efficient synthetic routes
comprising 21 and 20 linear steps from commercially available
(S)-(−) propylene oxide and L-aspartic acid with 2.5% and 3.3%
overall yield, respectively. We successfully installed a conjugated
diene and a carbonyl conjugated olefin with definite geometry
within 14-membeded macrocycles for the first time. Further-
more, our synthetic journey revealed that the reported structure
(5) of pestalotioprolide F is not accurate. We hereby revise the
structure (20) of pestalotioprolides F where the configurations
of C and C hydroxylated centers are opposite to the currently
1
5a
compound 22,
aspartic acid
prepared from commercially available L-
(Scheme 4), which was converted to its
corresponding sulfone using DIAD/Ph P/PTSH followed by
1
5b
3
4b
(
NH ) Mo O ·4H O/H O . The sulfone was treated with
4 6 7 24 2 2 2
CSA/MeOH to get the corresponding TBS deprotected
product, which was protected as TES ether using TESOTf/
2
,6-lutidine. The TES ether was then subjected to Julia-
4b,16 12a
Kocienski olefination
with the known aldehyde 23 to
4
9
get the corresponding E-olefin exclusively. The olefin was
accepted structure (5) of the molecule.
C
DOI: 10.1021/acs.orglett.8b01894
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
11) (a) Revu, O.; Prasad, K. R. J. Org. Chem. 2017, 82, 438−460.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
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and HRMS of representative compounds, and 2D-NMR
data (COSY, HSQC, HMBC, ROESY) of compounds 4,
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AUTHOR INFORMATION
Corresponding Author
E-mail: ocrkg@iacs.res.in.
■
*
ORCID
Rajib Kumar Goswami: 0000-0001-7486-0618
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.P. and S.S. thank the Council of Scientific and Industrial
Research, New Delhi for the research fellowship. The financial
support from Science and Engineering Research Board (Project
no. EMR/2016/000988), DST, India, to carry out this work is
gratefully acknowledged.
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DOI: 10.1021/acs.orglett.8b01894
Org. Lett. XXXX, XXX, XXX−XXX