Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

Article abstract of DOI:10.1016/j.tetlet.2017.05.034

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.

Full text of DOI:10.1016/j.tetlet.2017.05.034

Accepted Manuscript
Studies towards the total synthesis of cruentaren A and B: Stereoselective syn-
thesis of fragments C1-C11, C12-C22 and C23-C28
Bogonda Ganganna, Pabbaraja Srihari, Jhillu Singh Yadav
PII:
S0040-4039(17)30613-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.034
TETL 48927
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
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3 May 2017
11 May 2017
Please cite this article as: Ganganna, B., Srihari, P., Yadav, J.S., Studies towards the total synthesis of cruentaren
A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.05.034
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Tetrahedron Letters
Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of
fragments C1-C11, C12-C22 and C23-C28
Bogonda Ganganna,a,b,c Pabbaraja Sriharia,b and Jhillu Singh Yadava,b,*
aAcademy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110001, India.
bDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
cCollege of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil Chuncheon, Gangwon-do 24341, Republic of Korea.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28
fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the
strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate
anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-
dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated
aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22
fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-
butyne-1,4-diol and cis-2-butene-1,4-diol respectively.
Available online
Keywords:
Resorcylic acid lactones
Sharpless epoxidation
Alder-Rickert reaction
Pirrung-Heathcock’s aldol
2016 Elsevier Ltd. All rights reserved.
Resorcylic acid lactones (RAL) are common structural motifs
found in a numerous natural products,1 many of them exhibits
broad biological profile such as antifungal,2 antimalarial,
antiviral, antiparasitic,3 cytotoxic,4 oestrogenic,5 nematicidal,6
protein tyrosine kinase and ATPase inhibition activities.7 In 2006,
Hӧfle and co-workers isolated naturally occurring macrolactones
cruentaren A (1) and B (2) (Figure 1) from myxobacterium
ByssoVorax cruenta. Cruentaren A (1) strongly inhibits the
growth of yeast and filamentous fungi, shows high cytotoxicity
towards L929 mouse fibroblast cells with an IC50 value of 1.2 ng
mL-1,8,9 and selectively inhibits mitochondrial F-ATPase, and its
ring contracted congener cruentaren B (2) showed only minimal
cytotoxicity and no antifungal activity.9 These distinctive
biological activities, as well as its fascinating chemical
architecture, have attracted the attention of synthetic chemists.
Maier10 and Fürstner11 independently reported the total synthesis
of cruentaren A (1) in 2007. After this, two more total synthesis12
and their synthetic analogues have been published.10c,11b There is
only one total synthesis of cruentaren B (2) was reported by
Chakraborty et al.13 As part of our continued effort toward the
total synthesis of resorcylic acid lactones containing natural
products,14 we became interested in targeting these natural
products for their total synthesis. In this connection, we herein
report the synthesis of C1-C11, C12-C22 and C23-C28 key
fragments of cruentaren A (1) and B (2) by employing Sharpless
epoxidation, Alder–Rickert reaction and anti-aldol reaction
following Pirrung-Heathcock’s protocol as the key steps.
Figure 1. Structures of cruentaren A (1) and B (2).
to be synthesized from dienophile 6 through the Alder–Rickert
reaction. Acetylenic ester 6 can be derived from epoxide 7 by
regioselective epoxide opening with ethyl propiolate followed by
TBS protection. Compound 7, in turn, could be obtained from
epoxide
8
involving epoxide opening, TBS protection,
debenzylation followed by epoxide formation. Epoxide 8 could
be prepared from 2-butyne-1,4-diol using a Sharpless epoxidation
as one of the key steps. The C12-C22 fragment 4 was intended to
be accessed from oxetane 9 via oxetane opening, TBS protection
followed by TMS deprotection. Compound 9, in turn, could be
generated from propargyl alcohol 10 involving an aldol reaction
as the key step followed by reduction, tosylation and oxetane
formation. Alcohol 10 would be revealed from epoxide 11 by
involving epoxide opening with ethynyltrimethylsilane, TBS
Retrosynthetically, the cruentaren A (1) and B (2) can be
divided into three subunits are shown in scheme 1. Initially, we
planned to utilize an acetylide-triflate cross-coupling reaction
similar to that reported by Chakraborty and co-workers13 to
assemble the C1-C11 and C12-C22 fragments of cruentaren A
(1) and B (2). Accordingly, the C1-C11 fragment 3 was planned

Scheme 1. Retrosynthesis of cruentaren A (1) and B (2).
protection followed by primary TBS deprotection. Compound 11,
ether 14, and the benzyl ether was removed with Pearlman’s
catalyst in ethyl acetate provided 1,2-diol 15 in excellent yield.
The resulting diol 15 was readily converted to terminal epoxide 7
in one step by treating with 1-(p-toluenesulfonyl)imidazole and
NaH, which underwent opening with ethyl propiolate under
Yamaguchi conditions17 to deliver the propargylic ester 16 in
94% yield. Secondary alcohol 16 was protected to TBS ether by
treating with TBSOTf to afford acetylenic dienophile 6 in 91%
yield.
in turn, could be arisen from epoxide 12 via regioselective
epoxide opening, TBS protection, debenzylation followed by
terminal epoxide formation. Epoxide 12 could be synthesized
from cis-2-butene-1,4-diol using
a Sharpless asymmetric
epoxidation. The C23-C28 acid fragment 5 would be derived
from propargyl alcohol 10 through simple functional group
manipulations.
Our synthesis for functionalized C1-C11 aromatic subunit 3 is
depicted in scheme 2 and 3. Consequently, the synthesis
commenced from the known chiral epoxy alcohol 8, which was
readily accessed from commercially available 2-butyne-1,4-diol
in three steps using a literature procedure.15 Regio and
stereoselective opening of epoxide 8 was achieved in the
presence of Me3Al and n-BuLi give 1,3-diol 13 in 93% yield.16
The anti-diol 13 was selectively protected as its primary silyl
Having accessed dienophile 6 in hand, to construct highly
substituted aromatic precursor, we adopted to pursue the Alder-
Rickert reaction18 with diene 17 and dienophile 6 (Scheme 3).
o
The reaction was carried out in a sealed tube at 200 C with a
catalytic amount of N,N-dimethylaniline to generate the desired
product 3 in 48% yield. Deprotection of silyl ether 3 followed by
lactonization was achieved with TBAF in THF gave the
benzolactone fragment 18 of cruentaren B (2) in 91% yield.
Scheme 2. Synthesis of dienophile (6)

Scheme 3. Synthesis of C1-C11 fragment (3).
With the C1-C11 subunit in hand, we turned our focus to the
The stereochemistry of the aldol product was confirmed by
conversion to acetonide derivative 27 (Scheme 5). 13C NMR
spectrum of 27 shows signals at  99.0 ppm for a quaternary
carbon and at  19.7 and 29.9 ppm for the methyl carbons
confirms the presence of 1,3-syn stereochemistry.22
synthesis of C12-C22 polyketide fragment 4, beginning with
chiral epoxide 12 (scheme 4), which was obtained by the
protection of known cis-2-butene-1,4-diol followed by Sharpless
epoxidation in two steps.15 From here, the synthetic route
employed a similar sequence as applied in our earlier C1-C11
fragment to produce acetylenic compound 23. The primary TBS
group was selectively deprotected with 70% HF∙pyridine in THF
provided alcohol 10 in 86% yield. DMP oxidation19 of the
alcohol produced the corresponding aldehyde, which was
immediately treated with lithium enolate of dimethylphenyl
After acquiring the preferred structural configuration, we
proceeded further with the alcohol 26 for selective tosylation
with Et3N and tosyl chloride to obtain mono-tosylate 28 (scheme
o
6), which on exposure to n-BuLi in THF at 0 C afforded the
oxetane 9 in 83% yield. The TBS protected propargylic alcohol23
29 was metallated with n-BuLi and then treated with oxetane 9 in
the presence of BF3∙OEt2 as described by Yamaguchi24 delivered
the chiral homo-propargyl alcohol 30 in 81% yield. The alkynol
30 was protected as its corresponding silyl ether 31 with TBSOTf
in the presence of Hunig's Base in 89% yield. Selective
deprotection of trimethylsilyl group was achieved with K2CO3 in
o
propionate 24 in THF at -78 C under Pirrung-Heathcock’s aldol
protocol20 to obtain the desired anti-aldol product 25 in 68%
yield with good diastereoselectivity (93:7).21 Whereupon the ester
functionality was reduced with lithium aluminum hydride in
diethyl ether at -20 oC resulted in diol 26 in 78% yield.
methanol
resulted
alkyne
4
in
93%
yield.
Scheme 4. Synthesis of diol (26).
Scheme 5. Synthesis of acetonide derivative (27).

Scheme 6. Completion of C12-C22 fragment (4).
Scheme 7. Synthesis of C23-C28 acid fragment (5).
With the two key fragments in hand, we shifted our attention
Hofmann, T.; Altmann, K.-H. C. R. Chim. 2008, 11, 1318-
1335; (d) Bräse, S.; Encinas, A.; Keck, J.; Nising, C. F.
Chem. Rev. 2009, 109, 3903-3990; (e) Napolitano, C.;
Murphy, P. V. Resorcylic acid lactones. In Natural Lactones
and Lactams: Synthesis, Occurrence and Biological Activity;
Janecki, T., Ed.; Wiley-VCH: Weinheim, Germany, 2014;
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to synthesize the C23-C28 acid fragment 5 (Scheme 7), starting
from the readily available alkynol 10 in three steps. Removal of
the TMS group followed by hydrogenation with Pd/C gave the
alcohol 33 in 95% yield. Oxidation of primary alcohol with
TEMPO and BAIB25 afforded an acid 5 in 82% yield.
In conclusion, we have successfully accomplished the
synthesis of C1-C11, C12-C22 and C23-C28 fragments of
cruentaren A (1) and B (2). The C1-C11 aromatic precursor 3
was accessed in 7 steps from known chiral epoxide 8 using
Sharpless epoxidation and Alder-Rickert reaction as the key steps
with 28.5% overall yield and the C12-C22 polyketide fragment 4
was achieved in 15 steps from known epoxide 12 employing
Sharpless epoxidation, anti-aldol reaction following Pirrung-
Heathcock’s protocol and oxetane opening under Yamaguchi
conditions as the key steps with 11.6% overall yield. Total
synthesis of cruentaren A (1) and B (2) are our future interest and
efforts in this direction are currently underway.
2. Ayer, W. A.; Lee, S. P.; Tsuneda, A.; Hiratsuka, Y. Can. J.
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Acknowledgements
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B.G thanks CSIR, New Delhi for financial assistance in the form
of fellowship. JSY thanks CSIR and DST, New Delhi for
Bhatnagar and J. C. Bose Fellowships respectively. This work is
partly funded by CSC-0108, ORIGIN under XII Five Year Plan
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Supplementary data
1
Experimental procedures, Spectral data and Copies of H NMR,
13C NMR spectra of all compounds are available.
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Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis
of fragments C1-C11, C12-C22 and C23-C28
Bogonda Gangannaa,b,c Pabbaraja Sriharia,b and Jhillu Singh Yadava,b,*
aAcademy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110001, India.
bDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
cCollege of Pharmacy, Kangwon National University, 1 Kangwondaehak-gil Chuncheon,
Gangwon-do 24341, Republic of Korea.

Highlights

Three key fragments C1-C11, C12-C22 and C23-C28 of cruentaren were
synthesized


Achieved Pirrung-Heathcock’s anti aldol reaction with good diastereoselectivity
Regioselective Alder-Rickert reaction was successfully utilized for aromatic
fragment


C1-C11 fragment was accomplished very effectively with 25.8% overall yield
C12-C22 fragment was accomplished very efficiently which have four stereo
centers in 15 linear steps with 11.6% overall yield