Total synthesis of cytotoxic pyranone B

Article abstract of DOI:10.1080/00397911.2018.1536787

The first stereoselective total synthesis of cytotoxic diacetylene pyranone B is described. The key steps involved in the synthesis are base-induced elimination protocol to generate the chiral acetylenic alcohol and selective cross-coupling of unsymmetrical terminal acetylenes.

Full text of DOI:10.1080/00397911.2018.1536787

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Total synthesis of cytotoxic pyranone B
Uma Maheshwar Gonela, Suresh Kanikarapu & Jhillu S. Yadav
To cite this article: Uma Maheshwar Gonela, Suresh Kanikarapu & Jhillu S. Yadav (2018): Total
synthesis of cytotoxic pyranone B, Synthetic Communications
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https://doi.org/10.1080/00397911.2018.1536787
Total synthesis of cytotoxic pyranone B
Uma Maheshwar Gonelaa, Suresh Kanikarapua, and Jhillu S. Yadava,b
aNatural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India;
bSchool of Science, Indrashil University, Kadi, India
ABSTRACT
ARTICLE HISTORY
Received 2 July 2018
The first stereoselective total synthesis of cytotoxic diacetylene pyra-
none B is described. The key steps involved in the synthesis are base-
induced elimination protocol to generate the chiral acetylenic alcohol
and selective cross-coupling of unsymmetrical terminal acetylenes.
KEYWORDS
Diacetylene; cytotoxic; base-
induced elimination;
Cadiot–Chodkiewicz cross-
coupling; Sonogashira
cross-coupling
GRAPHICAL ABSTRACT
Introduction
Diacetylene containing molecules display a variety of biologically activities such as cyto-
toxic, antitumor, antiviral, antibiotic and antifungal activities.[1] For example, Iguchi
and coworkers isolated Strongylodiols 1–6 from the Okinawan marine sponge of the
genus strongylohora, which shows potent cytotoxic activity towards human T-lympho-
cyte leukaemia (MOLT-4) cells, IMR-90 and DLP-1 cell.[2] Panaxytriol 7 showed inhibi-
tory activity against MK-1 cells with an IC50 of 8.5 ng/mL and suppressed the growth
of B16 melanoma cells in mice.[3]
Very recently, unprecedented acetylenic natural products, pyranones 8–10 were iso-
lated by Hu et al. from cultures of junghuhnianitida. All exhibit significant activity
against five human cancer cell lines: breast cancer MCF-7, hepatocellular carcinoma
SMMC-7721, human myeloid leukemia HL-60, colon cancer SW480, and lung cancer
A-549 cells (Figure 1).[4]
In continuation of our program toward the development of new protocols and their
applications in the total synthesis of biologically potent natural products,[5,6] we herein
describe the first total synthesis of pyranone B (8).
CONTACT Jhillu S. Yadav
yadavfna@gmail.com; jsyadav@indrashiluniversity.edu.in
Natural Products Chemistry
Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; School of Science, Indrashil University,
Kadi 382740, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher's website.
ß 2018 Taylor & Francis Group, LLC

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U. MAHESHWAR GONELA ET AL.
Figure 1. Structures of strongylodiols, panaxytriol, and pyranones.
Scheme 1. Retrosynthesis of Pyranone B (8).
As per our retrosynthetic analysis outlined in Scheme 1, acetylenic bond disconnec-
tion furnishes the two terminal acetylenes. The key fragment could be stereoselectively
synthesized using our base-induced elimination protocol for the construction of chiral
propargylic alcohols. These fragments would be accessible from the commercially avail-
able (L)-ethyl lactate and the homopropargyl alcohol.
Results and discussion
The chiral bromoalkyne fragment 11 was synthesized in a stereoselective manner
starting from commercially available (L)-ethyl lactate. TBS protected (L)-ethyl lactate
(15) was converted to the aldehyde with DIBAL-H at −78 °C.[6] It was treated with
two carbon Wittig-ylide to furnish the α,β-unsaturated ester 16. The ester was con-
verted to corresponding allylic alcohol with DIBAL-H, which was subjected to the
Sharpless asymmetric epoxidation. Furthermore, the epoxy alcohol 17 was converted
to its epoxy chloride using CCl4-Ph3P at reflux conditions, which was then subjected
to a base-induced elimination protocol in presence of n-BuLi to give the chiral acety-
lenic alcohol 13.[6] Newly generated hydroxyl group was protected as its TBDPS
ether with TBDPSCl and imidazole to obtain 18 in 94% yield. The free terminal
acetylene 18 was brominated with NBS and catalytic AgNO3 to give 11 in 96% yield
(Scheme 2).[7]

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Scheme 2. Synthesis of fragment 11.
Scheme 3. Synthesis of fragment 20.
Another coupling partner alkyne 12 was prepared from readily available homopro-
pargyl alcohol 19 using TBSCl and imidazole, which was further brominated using NBS
and catalytical AgNO3 to afford 20 in 95% yield for two steps (Scheme 3).
In general, alkynyl electrophiles readily participated in Cu-catalyzed
Cadiot–Chodkiewicz[8] and Pd-catalyzed alkyne-alkyne cross couplings,[9] where
undesired homocoupling is the main problem in these cross-couplings.
Our preliminary experiment using standard conditions of Cadiot–Chodkiewicz with
the combination of 11 and 12 furnished the target compound in moderate yields along

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U. MAHESHWAR GONELA ET AL.
Table 1. Cross-coupling of terminal acetylenes.
S. No.
R1
R2
R3
Conditionsa
Yield %b
1
2
3
4
5
Br
H
Br
H
H
Br
H
Br
H
-TBS
-TBS
-TBS
-TBS
-H
CuCl, NH2OH.H2O, n-BuNH2.H2O
CuCl, NH2OH.H2O, n-BuNH2.H2O
Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF
Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF
Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF
68
72
79
91
83
Br
aAlkyne (1eq.), Bromo alkyne (1.2 eq.).
bIsolated yields.
Scheme 4. Accomplishment of 8.
with the homocoupling products in 17% yields (Table 1, entry 1). Likewise combining
18 and 20 led to improved yields (entry 2). Interestingly, the coupling reaction with
modified Sonogashira conditions (Table 1, entries 3–5)[9] gave the desired cross-cou-
pling product in better yields, along with lowering the homocoupling of alkyne.
Improved selectivity was observed with the less substituted bromoalkyne which was in
an excess amount.
Lastly, the accomplishment of the total synthesis of pyranone B (8) was achieved by
the treatment of TBAF on silyl protected compounds 21/22 in 84/89% yields respect-
1
27
ively (Scheme 4). The H and 13C NMR spectra and the specific rotation ([α]D −25.9
(c = 0.5, MeOH)), lit.[4] ([α]D −27.5 (c = 0.22, MeOH)) were consistent with those of
27
the natural product 8.
Experimental section
General experimental details
Solvents were dried over standard drying agents and freshly distilled prior to use. All
commercially available chemicals were used without further purification. All reactions
1
were performed under Nitrogen. H NMR and 13C NMR spectra were measured with

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5
Varian Gemini FT 200 MHz spectrometer, Bruker Avance 300 MHz, Unity 400 MHz
and Inova 500 MHz with tetramethylsilane as an internal standard for solutions in
CDCl3, J values are given in Hz. Chemical shifts were reported in ppm relative to the
solvent signal. All column chromatographic separations were performed using silica gel
(Acme’s, 60–120 mesh). Organic solutions were dried over anhydrous Na2SO4 and con-
centrated below 40 °C in vacuo. IR-spectra were recorded on FT IR (Perkin-Elmer IR-
683) spectrophotometer with NaCl optics. JASCO DIP 300 digital polarimeter was used
for measurement of optical rotations at 25 °C. Mass spectra were recorded on direct
inlet system or LC by MSD trap SL (Agilent Technologies), the HRMS data were
obtained using Q-TOF mass spectrometry.
(7R,8S)-nona-3,5-diyne-1,7,8-triol 8
To a solution of 21(40 mg, 0.062 mmol) in THF (2 mL) at 0 °C, TBAF (0.28 mL, 0.28
mmol, 1 M in THF) was added and the reaction mixture was stirred for 2 h at room
temperature. After completion of the reaction (monitored by TLC), it was quenched
with a saturated solution of NH4Cl (5 mL) and diluted with ethyl acetate (5 mL). The
layers were separated and the aqueous layer extracted twice with ethyl acetate. The com-
bined organic layer was dried over Na2SO4 and concentrated under reduced pressure,
and the crude product was purified by silica gel chromatography (methanol/chloroform
27
= 1:9) to afford 8 (8.8 mg, 84%) as a colorless liquid. [α]D −25.9 (c = 0.5, MeOH); IR
1
(neat): ν 2918, 2899, 1693, 1511, 1469, 1433, 1383, 1270, 962, 771 cm−1; H NMR (500
MHz, MeOD):δ 4.19 (d, J = 4.5 Hz, 1H), 3.74 (m, 1H), 3.64 (t, J = 6.6 Hz, 2H), 2.49 (t,
J = 6.6 Hz, 2H), 1.20 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (75 MHz, MeOD):δ 78.8, 76.1,
71.3, 70.9, 68.1, 66.4, 61.1, 24.0, 18.4 ppm; HRMS (ESI): m/z calcd.for C9H13O3 [M +
H]+ 169.0868; found: 169.0859.
Conclusion
In summary, the synthesis of pyranone B was accomplished with a longest linear
sequence of nine steps in 33% overall yield, starting from commercially available (L)-
ethyl lactate. It is anticipated that the synthesis in the strategy described herein will offer
access to other pyranone analogs and also predicted that the synthetic methods devel-
oped may have value in our further ventures.
Funding
U.M.G., S.K. thanks UGC and CSIR, New Delhi, India for financial assistance in the form of
fellowships.
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