Synthesis of the southern furan segment of furanocembranoids

Article abstract of DOI:10.1080/00397911.2019.1587780

A convergent synthesis of the southern furan segment of novel furanocembranoids from Croton oblongifolius has been accomplished involving silver-catalyzed cyclization of alkynyl diol as the key step towards 2, 5-disubstituted furan ring formation.

Full text of DOI:10.1080/00397911.2019.1587780

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of the southern furan segment of
furanocembranoids
Chada Raji Reddy, Siddique Z. Mohammed, Krishna Gaddam & Y. Lakshmi
Prapurna
To cite this article: Chada Raji Reddy, Siddique Z. Mohammed, Krishna Gaddam & Y. Lakshmi
Prapurna (2019): Synthesis of the southern furan segment of furanocembranoids, Synthetic
Communications, DOI: 10.1080/00397911.2019.1587780
To link to this article: https://doi.org/10.1080/00397911.2019.1587780
View supplementary material
Published online: 02 Apr 2019.
Submit your article to this journal
Article views: 5
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1587780
Synthesis of the southern furan segment of
furanocembranoids
Chada Raji Reddya,b, Siddique Z. Mohammeda,b, Krishna Gaddama, and
Y. Lakshmi Prapurnaa
aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology,
b
Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
ABSTRACT
ARTICLE HISTORY
Received 24 January 2019
A convergent synthesis of the southern furan segment of novel fura-
nocembranoids from Croton oblongifolius has been accomplished
involving silver-catalyzed cyclization of alkynyl diol as the key step
towards 2, 5-disubstituted furan ring formation.
KEYWORDS
Alkyne; cycloisomerization;
furan; furanocembranoid;
silver catalyst
GRAPHICAL ABSTRACT
Introduction
Khanitha and coworkers identified numerous cytotoxic diterpenoids from Croton oblon-
gifolius, which was used as a folk medicine to treat gastric cancers and ulcers.[1] In
2007, they had isolated novel 14-membered macrocycles called furanocembranoids 1-3
(Figure 1a–c) from the hexane extract of the stem bark of Croton oblongifolius.[2]
Eccentrically, the macrocylic frame of these natural products is linked to C2 and C4
positions of furan ring without five-membered lactone, whereas all the natural furano-
cembranoids has C2 and C5 linkage to furan with a five-membered lactone.[3]
Furanocembranoid 1 (1a) and 3 (1c) exhibited cytotoxicity against human tumor cell
lines such as BT474 (breast ductal carcinoma), CHAGO (undifferentiated lung carcin-
oma), Hep-G2 (liver hepatoblastoma), KATO-3 (gastric carcinoma), and SW-620 (colon
adrenocarcinoma).[2] The unusual structural feature of novel furanocembranoids 1–3
combined with their biological activity motivated us to explore the synthesis of this
molecule. Till date, there are no reports on synthetic efforts toward these novel furano-
cembranoids, except our recent work wherein fully functionalized acyclic carbon
CONTACT Chada Raji Reddy
rajireddy@iict.res.in
Department of Organic Synthesis and Process Chemistry, CSIR-
Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007 India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
C. RAJI REDDY ET AL.
Figure 1. Structures of natural furanocembranoids 1 to 3.
Scheme 1. Retrosynthetic analysis of furanocembranoid 1.
framework has been reported.[4] In this strategy, we were unsuccessful in ring-closing
metathesis reaction to complete the total synthesis. Herein, we present the successful
realization of our endeavors in our alternative strategy through the synthesis of the
southern furan fragment of furanocembranoids.
Results and discussions
The retrosynthetic analysis of furanocembranoids is described in Scheme 1. We envi-
sioned our first target furanocembranoid 1 (1a) to be obtained from the coupling of
furan fragment 2 with cyclic phosphonamide 3 through phosphonamide-anion olefina-
tion[5] and intramolecular Horner–Wadsworth–Emmons cyclization[6] as the key steps.
Furan fragment 2 could be accessed from the coupling of keto-fragment 4 and the
alkyne subunit 5 followed by the cyclization of alkynyl-diol. Ketone 4 could be gener-
ated from readily accessible b-keto-phosphonate 6 and commercially available diethyl 2-
isopropylmalonate 7.
As planned, the synthesis of ketone fragment 4 started with the diethyl 2-isopropyl-
malonate 7, which was subjected to LiAlH4-mediated reduction followed by selective

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 2. Synthesis of ketone fragment 4.
Scheme 3. Synthesis of furan segment of furanocembranoid.
silylation using TBDPSCl to give the mono-silylated alcohol 8 in 85% over two steps
(Scheme 2). Oxidation of the primary alcohol 8 using DMP in CH2Cl2 provided the
corresponding aldehyde, which was subjected to Horner-Wittig olefination with b-keto
phosphonate 6[7] in the presence of Ba(OH)2.8H2O in wet THF to give the enone 9 in
73% yield over two steps. Next, the reduction of an olefin of the enone 9 in the pres-
ence of Pd/C under H2 atmosphere in EtOAc delivered the saturated ketone 4 in 98%
yield (Scheme 2). The synthesis of the protected alkyne 5 has been accomplished follow-
ing the reported three-step protocol involving opening of methyloxirane with lithiated-
trimethylsilyl acetylene, p-methoxybenzyl (PMB) protection followed by desilylation.[8]
Having both the intermediates 4 and 5 in hand, we performed the addition of alkyne
on to the ketone to make the alkynyl-diol, key precursor for furan ring formation
(Scheme 3). Thus, treatment of ketone subunit 4 with lithiated-alkyne, generated from 5
using nBuLi, at ꢀ78 ꢁC afforded the propargyl alcohol 10 in 86% yield. Selective depro-
tection of tert-butyldimethyl silyl (TBS) ether in the presence of PPTS produced the
diol 11 in 90% yield. Pleasingly, AgNO3-catalyzed cycloaddition[9] of the alkynyl diol 11
in CH2Cl2 at room temperature, provided the desired 2,4-disubstituted furan 12 in 90%

4
C. RAJI REDDY ET AL.
yield. The deprotection of tert-butyldiphenyl silyl (TBDPS) ether with TBAF at room
temperature in THF furnished the furan 2, exemplifying the entire southern part of fur-
anocembranoid, in 88% yield.
Conclusion
In summary, we have achieved the convergent synthesis of the furan subunit (southern
fragment) of structurally novel furanocembranoids. This work demonstrates the utility
silver-catalyzed cyclization of alkynyl diol, which facilitated the rapid construction of
2,4-disubstituted furan framework. We believe that the present approach is scalable to
complete the total synthesis of furanocembranoids.
Experimental
All the reagents and solvents were purified by usual methods. Reactions were executed
in oven-dried round bottom flasks. Crude products were purified by column chroma-
tography on silica gel. Reactions were monitored by thin-layer chromatography.
1
Organic solutions were distilled on a rotary evaporator. H and 13C NMR spectra were
recorded in CDCl3 solvent on 400 and 500 MHz NMR spectrometers, respectively, at
ambient temperature and calibrated against the residual solvent peak. Chemical shifts
are reported in parts per million (ppm). Coupling constants (J) are quoted in hertz
(Hz). FTIR spectra were recorded on KBr thin films (for liquids). Mass spectra recorded
on micro mass VG 70–70 H or LC/MSD trap SL spectrometer operating at 70 eV using
direct inlet system. HRMS were recorded on quadrupole time-of-flight (Q-TOF) mass
spectrometer equipped with an ESI source.
tert-Butyl(2-isopropyl-4-(5-(2-(4-methoxybenzyloxy)propyl)furan-3-
yl)butoxy)diphenylsilane (12)
To solution of propargylic diol 11 (1.6 g, 2.6 mmol) in CH2Cl2 (20 mL), AgNO3
(529 mg, 3.12 mmol) was added at room temperature, stirring continued for 2 h.
Reaction mixture was diluted with water and extract with CH2Cl2 (20 mL) washed with
brine, dried over anhydrous Na2SO4. The crude mixture was subjected to silica gel col-
umn chromatography (0.5:9.5 ¼ EtOAc:hexanes) to afford the furan 12 (1.5 g, 95%) as
colorless oil. (Rf = 0.4, 9.5:0.5 hexanes:ethyl acetate). IR (neat): 2958, 2866, 1769, 1456,
1
1251, 1108, 1034, 704 cmꢀ1. H NMR (CDCl3, 400 MHz): d 7.67 (dt, J ¼ 7.9, 1.7 Hz,
4H), 7.45–7.33 (m, 6H), 7.23–7.18 (m, 2H), 7.01 (s, 1H), 6.87–6.81 (m, 2H), 5.91 (s,
1H), 4.44 (q, J ¼ 11.4 Hz, 2H), 3.81–3.73 (m, 4H), 3.64–3.58 (m, 2H), 2.89 (ddd,
J ¼ 14.9, 6.0, 1.3 Hz, 1H), 2.67 (dd, J ¼ 14.8, 6.7 Hz, 1H), 2.40–2.18 (m, 2H), 1.95–1.84
(m, 1H), 1.60–1.49 (m, 4H), 1.36 (dt, J ¼ 10.5, 5.3 Hz, 1H), 1.19 (t, J ¼ 5.0 Hz, 3H), 1.05
(d, J ¼ 2.7 Hz, 9H), 0.89–0.81 (m, 6H). 13C NMR (CDCl3, 100 MHz): d 159.1, 153.1,
137.1, 135.7, 134.0, 134.0, 130.9, 129.6, 129.2, 127.6, 126.3, 113.8, 108.3, 73.5, 70.3, 64.4,
55.3, 46.0, 35.6, 28.2, 28.1, 26.9, 23.3, 20.1, 19.9, 19.3. MS (ESI): m/z 621 (M þ Na)þ.
HRMS (ESI): m/z calcd for C38H50O4SiNa (M þ Na)þ: 621.3371, found: 621.3355.

R
SYNTHETIC COMMUNICATIONSV
5
2 -Isopropyl-4-(5-(2-(4-methoxybenzyloxy)propyl)furan-3-yl)-butan-1-ol (2)
To a solution of 12 (1.3 g, 2.2 mmol) in THF (40 mL), was added TBAF (1.0 M in THF,
2.64 mL, 2.64 mmol) and stirred for 1.5 h. The reaction mixture was quenched with aq.
NH4Cl solution (20 mL), extracted with EtOAc (3 ꢂ 10 mL). Solvent was evaporated
under reduced pressure and purified by SiO2 column (EtOAc:hexane = 1:9) to give 2
(836 mg, 88%) colorless oil (Rf = 0.5, 2:1 ¼ hexanes:ethyl acetate). IR (neat): 3435, 2958,
1
2876, 1723, 1514, 1461, 1249, 971, 825 cmꢀ1. H NMR (CDCl3, 400 MHz): d 7.21 (d,
J ¼ 8.5 Hz, 2H), 7.09 (s, 1H), 6.85 (d, J ¼ 8.6 Hz, 2H), 5.96 (s, 1H), 4.44 (q, J ¼ 11.4 Hz,
2H), 3.83–3.73 (m, 4H), 3.67–3.55 (m, 2H), 2.89 (dd, J ¼ 14.9, 6.1 Hz, 1H), 2.68 (dd,
J ¼ 14.9, 6.6 Hz, 1H), 2.51–2.31 (m, 2H), 1.84 (tt, J ¼ 13.6, 6.9 Hz, 1H), 1.65–1.45 (m,
3H), 1.41–1.32 (m, 1H), 1.20 (d, J ¼ 6.1 Hz, 3H), 0.90 (dd, J ¼ 6.9, 1.5 Hz, 6H). 13C
NMR (CDCl3, 100 MHz): d 159.1, 153.2, 137.1, 130.9, 129.2, 128.7, 126.1, 113.9, 113.8,
108.2, 77.4, 77.0, 76.7, 73.5, 70.3, 63.6, 55.3, 46.1, 35.5, 28.2, 27.9, 23.3, 19.9, 19.8, 19.3.
MS (ESI): m/z 383 (M þ Na)þ. HRMS (ESI): m/z calcd for C22H32O4Na (M þ Na)þ:
383.2198, found: 383.2202.
Funding
CRR thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for financial
support as part of XII-five year plan project under title ORIGIN (CSC-108). YLP thanks
Department of Science and Technology (DST), Ministry of Science and Technology for financial
grant under Women Scientists Scheme-A (WOS-A), Grant No. SR/WOS-A/CS-108/2017 (G).
SZM and GK thank the Council of Scientific and Industrial Research (CSIR), New Delhi for
research fellowship [Communication No. IICT/Pubs./2019/074].
References
[1] (a) Roengsumran, S.; Musikul, K.; Petsom, A.; Vilaivan, T.; Sangvanich, P.; Pornpakakul,
S.; Puthong, S.; Chaichantipyuth, C.; Jaiboon, N.; Chaichit, N. Croblongifolin, a New
Anticancer Clerodane from Croton Oblongifolius. Planta Med. 2002, 68, 274. DOI:
10.1055/s-2002-23138. (b) Roengsumran, S.; Petsom, A.; Kuptiyanuwat, N.; Vilaivan, T.;
Ngamrojnavanich, N.; Chaichantipyuth, C.; Phuthong, S. Cytotoxic Labdane Diterpenoids
from Croton oblongifolius. Phytochemistry 2001, 56, 103. DOI: 10.1016/S0031-
9422(00)00358-7. (c) Roengsumran, S.; Petsom, A.; Sommit, D.; Vilaivan, T. Labdane
Diterpenoids from Croton oblongifolius. Phytochemistry 1999, 50, 449. DOI: 10.1016/
S0031-9422(98)00604-9. (d) Roengsumran, S.; Singtothong, P.; Pudhom, K.;
Ngamrochanavanich, N.; Petsom, A.; Chaichantipyuth, C. . Neocrotocembranal from
Croton oblongifolius. J. Nat. Prod. 1999, 62, 1163. DOI: 10.1021/np9900268. (e)
Roengsumran, S.; Achayindee, S.; Petsom, A.; Pudhom, K.; Singtothong, P.; Surachetapan,
C.; Vilaivan, T. Two New Cembranoids from Croton Oblongifolius. J. Nat. Prod. 1998,
61, 652.
[2] Pudhom, K.; Vilaivan, T.; Ngamrojanavanich, N.; Dechangvipart, S.; Sommit, D.; Petsom,
A.; Roengsumran, S. Furanocembranoids from the Stem Bark of Croton oblongifolius.
J. Nat. Prod. 2007, 70, 659. DOI: 10.1021/np060520t.
[3] (a) Craig, R. A., II.; Stoltz, B. M. Polycyclic Furanobutenolide-Derived Cembranoid and
Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts. Chem.
Rev. 2017, 117, 7878. DOI: 10.1021/acs.chemrev.7b00083. (b) Li, Y.; Pattenden, G.
Perspectives on the Structural and Biosynthetic Interrelationships between Oxygenated

6
C. RAJI REDDY ET AL.
Furanocembranoids and Their Polycyclic Congeners Found in Corals. Nat. Prod. Rep.
2011, 28, 1269. DOI: 10.1039/c1np00023c.
[4] Reddy, C. R.; Mohammed, S. Z. Synthetic Studies toward ( )-Furanocembranoid 1:
Construction of the Acyclic Carbon Framework. ACS Omega 2018, 3, 15628. DOI:
10.1021/acsomega.8b02328.
[5] (a) Focken, T.; Hanessian, S. Application of Cyclic Phosphonamide Reagents in the Total
Synthesis of Natural Products and Biologically Active molecules. Beilstein J. Org. Chem.
2014, 10, 1848. DOI: 10.3762/bjoc.10.195. (b) Hanessian, S.; Focken, T.; Oza, R. Total
Synthesis of Jerangolid A. Org. Lett. 2010, 12, 3172. DOI: 10.1021/ol101103q. (c) Fang, G.;
Bi, X. Silver-Catalysed Reactions of Alkynes: Recent Advances. Chem. Soc. Rev. 2015, 44,
8124. DOI: 10.1039/C5CS00027K.
[6] (a) Schmidt, R.; Ostermeier, M.; Schobert, R. Wittig Cyclization of x-Hydroxy
Hemiacetals: Synthesis of (þ)-Aspicilin. J. Org. Chem. 2017, 82, 9126. DOI: 10.1021/acs.
joc.7b01702. (b) Raghavan, S.; Sreekanth, T. Stereoselective Total Synthesis of
(þ)-Aspicilin. Tetrahedron Lett. 2006, 47, 5595. DOI: 10.1016/j.tetlet.2006.05.043. (c)
Kennedy, R. M.; Abiko, A.; Takemasa, T.; Okumoto, H.; Masamune, S. A Synthesis of 19-
Dehydroamphoteronolide b. Tetrahedron Lett. 1988, 29, 451. DOI: 10.1016/S0040-
4039(00)80119-7.
[7] Bates, R. W.; Lek, T. G. A Synthesis of Cyanolide a by Intramolecular Oxa-Michael
Addition. Synthesis 2014, 46, 1731. DOI: 10.1055/s-0033-1341153.
[8] Miyatake-Ondozabal, H.; Barrett, A. G. M. Total Synthesis of TAK-kinase inhibitor LL-
Z1640-2 via consecutive macrocyclization and transannular aromatization. Org. Lett. 2010,
12, 5573. DOI: 10.1021/ol102468k.
[9] (a) Kalaitzakis, D.; Noutsias, D.; Vassilikogiannakis, G. First Total Synthesis of
Pandamarine. Org. Lett. 2015, 17, 3596. DOI: 10.1039/c1ob05567d. (b) Gryparis, C.;
Lykakis, I. N.; Efe, C.; Zaravinos, L. P.; Vidali, Y.; Kladou, E.; Stratakis, M. Functionalized
3(2H)-Furanones via Photooxygenation of (B-Keto)-2-Substituted Furans: Application to
the Biomimetic Synthesis of Merrekentrone C. Org. Biomol. Chem. 2011, 9, 5655. DOI:
10.1039/c1ob05567d. (c) Yoshimura, F.; Sasaki, M.; Hattori, I.; Komatsu, K.; Sakai, M.;
Tanino, K.; Miyashita, M. Synthetic Studies of the Zoanthamine Alkaloids: The Total
Syntheses of Norzoanthamine and zoanthamine. Chemistry 2009, 15, 6626. DOI: 10.1002/
chem.200900310.