Stereoselective Total Synthesis of Bioactive Marine Natural Product Biselyngbyolide B

Article abstract of DOI:10.1021/acs.orglett.6b00713

A convergent strategy for the stereoselective total synthesis of biologically active marine natural product biselyngbyolide B has been developed. Key strategies of this synthesis include Jamison protocol of trans-hydroalumination/allylation for installation of C₁₈-C₂₃ olefin moiety and intramolecular Heck coupling for macrocyclization.

Full text of DOI:10.1021/acs.orglett.6b00713

Letter
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of Bioactive Marine Natural Product
Biselyngbyolide B
Sayantan Das, Debobrata Paul, and Rajib Kumar Goswami*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
S
* Supporting Information
ABSTRACT: A convergent strategy for the stereoselective total synthesis of
biologically active marine natural product biselyngbyolide B has been
developed. Key strategies of this synthesis include Jamison protocol of trans-
hydroalumination/allylation for installation of C18−C23 olefin moiety and
intramolecular Heck coupling for macrocyclization.
uenaga and co-workers were the first to discover the
bioactive secondary metabolite biselyngbyaside 1 and its
congeners biselyngbyolide B 2, biselyngbyaside B 3, biselyng-
byolide A 4, biselyngbyaside C 5, and biselyngbyaside D 6
(Figure 1) during their bioassay-guided fractionation of
centers. The presence of several double bonds like allylic,
skipped, and conjugated olefins made this molecule synthetically
challenging. Maier et al.3 and Chandrasekhar et al.4 reported the
synthesis of the C1−C13 and C5−C23 segments of biselyngbya-
side 1, respectively. Suenaga et al.5 developed an elegant way to
achieve the total synthesis of biselyngbyolide A 4 through an
intramolecular Stille coupling based ring closing strategy. The
promising bioactivities of biselyngbyolide B 2, its natural scarcity,
its structural uniqueness, and our continued interest6 in the
synthesis of bioactive natural products prompted us to embark
on total synthesis of biselyngbyolide B 2; one of the most active
members of biselyngbyaside class of natural products. In this
letter, we disclose a highly convergent and flexible stereoselective
en route total synthesis of structurally intriguing biselyngbyolide
B 2 for the first time.
S
Retrosynthetic analysis of biselyngbyolide B 2 is summarized
in Scheme 1. The targeted molecule 2 could be constructed from
Scheme 1. Retrosynthetic Analysis of Biselynbyolide B 2
Figure 1. Structure of biselyngbyaside 1 and its congeners 2−6.
methanol extract of marine cyanobacterium Lyngbya sp.1
Biselyngbyaside 1 exhibits inhibitory activity against the growth
of human cervical cancer (HeLa) and leukemia (HL60) cells with
IC50 values of 2.5 and 0.31 μM, respectively.1c It also shows a
broad-spectrum of cytotoxicity against a series of different human
tumor cell lines in submicromolar concentration. Moreover,
biselyngbyaside 1 instigates the apoptosis of osteoclasts.2
Biselyngbyolide B 2, the aglycon part of biselyngbyaside 1,
shows 30- to 100-fold apoptosis-induction compared to
biselyngbyaside 1. In addition, biselyngbyolide B 2 acts as
endoplasmic reticulum stress inducer.1d Architecturally it is an
18-membered macrolide embedded with four stereogenic
Received: March 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00713
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Organic Letters
Letter
compound 7 by intramolecular macrocyclization using a Heck
coupling as one of the key steps.7 The Heck precursor 7 could be
accessed from alcohol 8 and acid 9 by intermolecular
esterification. The acid fragment 9 could be assembled from
coupling partners 10 and 11 using a Julia−Kocienski olefination8
as the key step.
species, at a low temperature (−20 °C). However, the formation
of unwanted SN2′ product 13a could not be further reduced
(Table 1, entry 5). The required olefin 13 mixed with its
inseparable counterpart 13a was oxidized by Dess−Martin
periodinane (DMP) and subsequently the crude reaction
mixture was separated by silica gel chromatography to obtain
aldehyde 14 in pure form. The aldehyde 14 was then subjected to
Brown allylation reaction10 using (+)-Ipc2B(allyl)borane to
produce 8 in enantiomerically enriched form (ee = 80%). The
ratio of enantiomers (8/ent-8) was determined unambiguously
The synthesis of intermediate 8 is depicted in Scheme 2. We
searched for a protocol that would yield the (C18−C23) olefin
Scheme 2. Synthesis of Intermediate 8
1
from the H NMR analysis of the corresponding inseparable
mixture of (S)-Mosher ester derivatives 15 and 15a (dr = 9:1).
Compound ent-8 was separated at the next stage of synthesis.
The synthesis of the requisite coupling partners 10 and 11 for
Julia−Kocienski olefination8 is described in Scheme 3. We
Scheme 3. Synthesis of Sulfone 10 and Aldehyde 11
moiety in one pot from readily available starting material. The
strategy developed by Jamison et al. where they have shown the
synthesis of substituted olefins directly from alkynols by Red-Al
assisted trans-hydroalumination/allylation sequence in the
presence of MeLi and Cu(I) source seemed most judicious.9
Accordingly we performed the reaction between 2-butyn-1-ol 12
and crotyl bromide 12a (Table 1, entry 1). The required olefin 13
Table 1. Optimization of Reaction between 2-Butyn-1-ol 12
and Crotyl Bromide 12a
total
ratio
entry
1
conditions
yield (%) (13/13a)
Red-Al, 0 °C−rt, 6 h, MeLi, 0 °C, 1.5 h, 12a,
CuCl, THF, 0 °C−rt, 2 h
Red-Al, 0 °C−rt, 6 h, MeLi, 0 °C, 1.5 h, 12a, 0
76
60
62
1.3:1
1:1
2
3
°C−rt, 2 h
Red-Al, 0 °C−rt, 6 h, 12a, CuCl, THF, 0 °C−rt,
1.4:1
2 h
4
5
Red-Al, 0 °C−rt, 6 h, 12a, 0 °C, 2 h
Red-Al, 0 °C−rt, 6 h, 12a, −20 °C, 5 h
71
60
2.3:1
2.3:1
started our synthesis from known compound 16,11 which was
oxidized to the corresponding aldehyde using Swern conditions
and concomitantly subjected to Wittig olefination using Ph3P
C(Me)CO2Et to get α,β-unsaturated ester 17 as the major
isomer (E/Z = 13:1), which was purified by silica gel column
chromatography. Careful reduction of ester 17 by DIBAL-H
provided the corresponding aldehyde, which, when subsequently
subjected to Crimmins acetate aldol12 using N-acetyl thiazolidi-
nethione 1812a in the presence of TiCl4 and Hunig’s base,
provided 19 as major isomer (dr = 5:1) with overall 72% yield.
The major isomer 19 was separated and then reduced to the
corresponding diol using NaBH4/MeOH, and the primary
alcohol group was selectively protected using TrCl/Et3N/
DMAP to get alcohol 20 in good overall yield (82% in two
steps). Next alcohol 20 was reacted with MeI/NaH to get the
corresponding O-methylated compound and subsequently
treated with TBAF to access alcohol 21. Alcohol 21 was then
oxidized to the corresponding aldehyde using IBX and
was obtained along with an inseparable mixture of isomerized
compound 13a in substantial amount (13/13a = 1.3:1), which
stipulates comparable participation of crotyl bromide in both SN2
and SN2′ type reactions. We have tried different reaction
conditions (Table 1) to reduce the formation of unwanted SN2′
product 13a. Neither the presence of MeLi nor CuCl improved
the ratios of olefins 13 and 13a (Table 1, entries 2 and 3).
Activation of either the Alanate species or crotyl bromide or the
both, substantially facilitated the SN2′ pathway. We decided to
attempt the reaction without any additives. The vinyl alane was
generated first from 2-butyn-1-ol 12 by treatment with Red-Al
and subsequently quenched with crotyl bromide 12a at 0 °C
(Table 1, entry 4). We were delighted to see that olefin 13
formed along with the isomerized compound 13a with much
improved ratio (13/13a = 2.3:1) and with an overall yield
comparable to Jamison’s condition9 (Table 1, entry 1). We
performed this reaction, specially the quenching of vinyl alane
B
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Letter
concomitantly subjected to Takai olefination13 using CHI3/
CrCl2. The crude reaction mixture was further treated with CSA
to result in iodoalcohol 22 as a major product (E/Z ≈ 4:1). The
minor Z-counterpart was found to be inseparable through a few
subsequent synthetic steps. The major product 22 was found to
be the required 12E-isomer as evident from its large coupling
constant between H12−H13 (J = 14.0 Hz). Alcohol 2214 was
reacted, first with PTSH 23 in the presence of DIAD/Ph3P
following Mitsunobu conditions15 to achieve the corresponding
sulfide,14 and then subsequently oxidized to sulfone 1014 using
(NH4)6Mo7O24·4H2O in the presence of 30% H2O2 with 76%
overall yield. However, the known epoxide 24, prepared from
commercially available D-aspartic acid following literature
protocol,16 was treated with Me3SI/n-BuLi17 to get allylic
alcohol 25, which was then protected as TBDPS ether and finally
subjected to oxidative cleavage to get aldehyde 11.
relative to Yamaguchi20 (33%) and EDCI21 conditions (28%).
The ester generated from ent-8, the minor impurity, was not
detectable. Ester 714 was finally subjected to a crucial
intramolecular macrocyclization using Heck coupling.7
A
number of reagent combinations (Table 2) were tested to
Table 2. Optimization of Intramolecular Heck Cross
Coupling for Macrocyclization
time
conditions (h)
entry
reagents
yield (%)
1
2
Pd(PPh3)4, Et3N, MeCN
60 °C
rt
3
3
decomposition
decomposition
PdCl2(MeCN)2, Et3N,
HCOOH, MeCN
a
3
4
PdCl2(PPh3)2, K2CO3,
Bu4NCl, DMF
60 °C
3
1
trace
b
Pd(OAc)2, K2CO3, Bu4NCl,
DMF
60 °C
58
The synthesis of acid 9 is depicted in Scheme 4. Sulfone 10 and
a
b
aldehyde 11 were subjected to Julia−Kocienski olefination.8 A
Product identified by mass spectroscopy. Only 12E/14E isomer was
detectable as the sole product.
Scheme 4. Synthesis of Acid Fragment 9
optimize the yield. We were indeed happy to observe that
Pd(OAc)2/K2CO3/Bu4NCl combination in DMF (Table 2,
entry 4) afforded cyclized compound 27 as a sole isolable
product (58%). We were not able to detect any cyclized product
during this process from the minor ester where the iodoolefin is
in Z- configuration. A detailed NMR study was carried out to
reassure the stereochemistry of the synthesized macrocycle 27.
The large coupling constants between H12−H13 and H14−H15 are
15.0 and 15.0 Hz, respectively, clearly indicate the trans-
geometry of the olefins embedded between C12−C13 and C14−
C15 segments. The transoid geometry of the conjugated diene was
confirmed further from observed NOESY correlations between
H11−H13 and H14−H16 protons. The characteristic COSY,
NOESY and HMBC correlations of synthesized macrocycle 27
unambiguously confirmed its structure (please see Supporting
Information). Finally the TBDPS ether of compound 27 was
removed efficiently using TBAF to produce biselyngbyolide B 2
in 96% yield. The spectral data of the synthesized compound is in
good agreement with the literature value reported by Suenaga et
al.1d (please see Table 1 in Supporting Information). The
number of bases (NaHMDS, KHMDS, LiHMDS, KOt-Bu) were
screened to optimize the conditions for efficient coupling.
KHMDS was found to be optimal with respect to selectivity (E/Z
= 6.2:1) and yield (71%). The major E-isomer 2614 was separated
from its minor Z-counterpart14 by silica gel chromatography and
subsequently subjected to primary TBS ether cleavage using CSA
to get the corresponding primary alcohol14 in good yield (78%).
The alcohol was then oxidized to aldehyde using IBX and
subjected to Pinnick oxidation18 to access the required acid 914 in
good overall yield (79%).
The final synthetic endeavor of biselyngbyolide B 2 is
illustrated in Scheme 5. The required allylic alcohol 8, mixed
with ent-8, and acid 914 were subjected to esterification to get the
advanced stage intermediate 714 as the major product. We have
screened a number of coupling reagents for this condensation. It
was observed that Shiina conditions19 (73%) were more effective
observed difference in the specific rotation {observed [α]29
D
−51.7 (c 0.48, CHCl3); reported [α]22D −240 (c 0.058, CHCl3)}
could not be reconciled at this point.
In summary, we have demonstrated a convergent and flexible
route for the total synthesis of bioactive natural product
biselyngbyolide B 2 for the first time from known compound
16. During this synthetic study, we discovered a new
modification of the Jamison protocol of trans-hydroalumina-
tion/allylation, a crucial step in the synthesis, which was found to
be more efficient in preparing the requisite olefin 13 than the
original. Finally, the strategic implementation of modified
Jamison protocol, Brown allylation, Wittig olefination, Crimmins
acetate aldol, Julia−Kocienski olefination, intermolecular Shiina
esterification, and intramolecular Heck cyclization protocol
render this synthesis efficient.
Scheme 5. Completion of Synthesis of Biselyngbyolide B
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00713.
C
DOI: 10.1021/acs.orglett.6b00713
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Organic Letters
Letter
(19) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 286.
(20) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106,
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(21) Hallside, M. S.; Brzozowski, R. S.; Wuest, W. M.; Phillips, A. J. Org.
Lett. 2014, 16, 1148.
Experimental procedures, spectroscopic data, copies of
NMR (1H and 13C) and HRMS of representative
compounds, 2D NMR data for compound 27 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ocrkg@iacs.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.D. and D.P. thank the Council of Scientific and Industrial
Research, New Delhi for research fellowships. The financial
support from the Department of Science and Technology
(Project no. SB/S5/GC-03/2013 and SR/FT/CS-157/2011),
India, to carry out this work is gratefully acknowledged
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DOI: 10.1021/acs.orglett.6b00713
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