Synthesis of CIS-fused bicyclic systems by radical cyclization approach: Formal synthesis of ethisolide and ISO-avenaciolide

Article abstract of DOI:10.1080/00397911.2013.871562

Formal synthesis of ethisolide and iso-avenaciolide was achieved using furanoid glycal-vinyl radical intermediates. The vinyl radical cyclization by 5-exo-dig mode gave the cis-fused bicyclic systems with an efficient introduction of the exo-methylene gro

Full text of DOI:10.1080/00397911.2013.871562

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Synthesis of cis-Fused Bicyclic Systems
by Radical Cyclization Approach:
Formal Synthesis of Ethisolide and iso-
Avenaciolide
Gangavaram V. M. Sharma a & Devoju Harinada Chary a
a Organic and Biomolecular Chemistry Division , CSIR Indian Institute
of Chemical Technology , Hyderabad , India
Published online: 14 May 2014.
To cite this article: Gangavaram V. M. Sharma & Devoju Harinada Chary (2014) Synthesis of cis-Fused
Bicyclic Systems by Radical Cyclization Approach: Formal Synthesis of Ethisolide and iso-Avenaciolide,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:12, 1771-1779, DOI: 10.1080/00397911.2013.871562
To link to this article: http://dx.doi.org/10.1080/00397911.2013.871562
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Synthetic Communications1, 44: 1771–1779, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.871562
SYNTHESIS OF CIS-FUSED BICYCLIC SYSTEMS BY
RADICAL CYCLIZATION APPROACH: FORMAL
SYNTHESIS OF ETHISOLIDE AND ISO-AVENACIOLIDE
Gangavaram V. M. Sharma and Devoju Harinada Chary
Organic and Biomolecular Chemistry Division, CSIR Indian Institute of
Chemical Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Formal synthesis of ethisolide and iso-avenaciolide was achieved using furanoid
glycal-vinyl radical intermediates. The vinyl radical cyclization by 5-exo-dig mode gave
the cis-fused bicyclic systems with an efficient introduction of the exo-methylene group,
besides helping in the inversion of the adjacent stereocentre. Further, the study describes
the synthesis of cis-fused bicyclic systems from L-arabinose and D-xylose for the creation
of diverse natural and synthetic products of this class.
Keywords Carbohydrates; 5-exo-dig; exo-methylene; furanoid glycal; radical cyclization
INTRODUCTION
Modern carbohydrate chemistry is a diverse discipline strongly connected with
organic and medicinal chemistry.[1] Nature uses diversity-oriented synthesis[2] (DOS),
whereby it designs molecules of skeletal, structural, stereochemical, and functional
diversity. Nature’s DOS is reflected by the presence of a variety of a-methylene
Received October 16, 2013.
Address correspondence to Gangavaram V. M. Sharma, Organic and Biomolecular Chemistry
Division, CSIR Indian Institute of Chemical Technology, Hyderabad, 500 007, India. E-mail: esmvee@
iict.res.in
1771

1772
G. V. M. SHARMA AND D. H. CHARY
Figure 1. Natural and synthetic products containing a-methylene-bis-butyrolactone skeletons.
bis-butyrolactones[3,4] 15 (Fig. 1), besides a variety of other natural products. These
natural products differ in the lengths of their side chains and the arrangements of the
bicyclic systems to result in diversely fused furo-furan systems.
In our earlier studies, a 5-exo-dig[5] radical cyclization approach was efficiently
utilized for the synthesis of this class of natural products[4] from diacetone glucose
(DAG). In these studies, the radical cyclization[6] was found to be very successful
in giving cis-fused bicyclic systems along with the concomitant introduction of
exo-methylene group.
Ethisolide 1[7] and iso-avenaciolide 2[8] are two bis-lactone class of secondary
metabolites isolated from the broths of Aspergillus avenaceus and Penicillium species
respectively. Both these compounds have been shown to inhibit fungal growth and
antibacterial activity.[9] The a-methylene-c-butyrolactone system was found to
impart biological activity to the natural products of this group. Structurally, 1 and
2 are similar, except for the length of their side chains.[10] In continuation of our
studies[11] on radical cyclization reactions en route to the bis-butyrolactone class
of natural products, herein we report our efforts on the synthesis of 1 and 2
(Fig. 1) with suitably substituted 5-vinyl radical,[12] which undergoes ring closure
by a 5-exo-dig mode preferentially.
RESULTS AND DISCUSSION
The retrosynthetic strategy for 1 and 2, as depicted in Scheme 1, revealed that
bicyclic systems 8 and 9 are the late-stage intermediates, which could be realized
from the glycal-vinyl radical intermediates 8a and 9a respectively. Such systems
can be generated from DAG 10. Thus, the main synthetic strategy is (a) to generate
C-3=C-4 glycal and (b) to utilize a vinyl radical for the radical cyclization to invert
the C-4 stereocenter, while creating the cis-fused bicyclic system.
Scheme 1. Retrosynthetic analysis of 1 and 2.

SYNTHESIS OF ETHISOLIDE AND ISO-AVENACIOLIDE
1773
Scheme 2. Synthesis of intermediates 15 and 16.
Accordingly, known[4a,4b] furanosides 11 and 12 on methanolysis with two to three
drops of concentrated HCl in methanol at temperatures ranging from 0 ꢀC to room tem-
perature gave diastereomeric mixtures of methyl glycosides 13 (1:1.5) and 14 (1:2.3)
respectively as a-anomers 13a (34%)=14a (25%) and b-anomers 13b (51%)=14b (57%).
Reactions of 13a/13b and 14a/14b independently with 2,3-dibromopropene in the
presence of NaH in dry tetrahydrofuran (THF) furnished the bromo derivatives 15a
(72%)=15b (78%) and 16a (65%)=16b (64%) respectively (Scheme 2).
The b-anomers 15b and 16b were independently subjected to oxidative deprotec-
tion of the p-methoxybenzyl (PMB) group with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) in aqueous CH2Cl2 to give the respective alcohols 17b (75%) and 18b (82%),
Scheme 3. Synthesis of compounds 1 and 2.

1774
G. V. M. SHARMA AND D. H. CHARY
Scheme 4. Retrosynthetic analysis of 23 and 24.
which on reaction with Tf2O and pyridine in dry CH2Cl2 at ꢁ20 ꢀC for 30 min gave
respective triflates 19 (95%) and 20 (93%) respectively (Scheme 3).
Treatment of 19 and 20 with DBU in dry dimethylsulfoxide (DMSO) at 0 ꢀC to
room temperature for 12 h afforded furanoid glycals 21a and 22a respectively, which,
on reaction[7d,12] with n-Bu3SnH in the presence of catalytic amount of azobisisobu-
tyronitrile (AIBN) in dry benzene at reflux for 12 h, afforded cis-fused bicyclic
systems 8 (71%) and 9 (65%) respectively. Further conversion of 8 and 9 to 1 and
2 has been reported in the literature,[7e] and the synthesis of 8 and 9 constitutes
the formal synthesis of 1 and 2 (Scheme 3).
Synthesis of Bicyclic Systems 23 and 24
Earlier, the synthesis of natural products such as xylobovide 3,[4e] canadensolide
4,[4d] and sporothriolide 5,[4b] besides synthetic products iso-canadensolide 6[13]
(Fig. 1) have been reported. In all our earlier approaches, the side chain was intro-
duced before the construction of cis-fused bicyclic systems. Hence, to create diverse
molecules, it was proposed to undertake the synthesis of cis-fused bicyclic systems
by 5-exo-dig radical cyclization from the precursors derived from L-arabinose and
D-xylose, so that the requisite side chains can be introduced appropriately on these
bicyclic systems for the synthesis of related natural and synthetic products.
According to the retrosynthetic strategy, the bicyclic systems 23 and 24 could
be made from the xanthates 27 and 28, through the radical precursors 25 and 26,
whereas the xanthate derivatives 27 and 28 in turn could be realized from
L-arabinose and D-xylose derivatives 29 and 30 respectively (Scheme 4).
Accordingly, known silyl ethers 29[14] and 30[15] on alkylation with propargyl
bromide in the presence of NaH in THF at room temperature for 4 h furnished
the propargyl ethers 31 (91%) and 32 (80%). Methanolysis of 31 and 32 with
concentrated HCl (catalyst) in MeOH at 0 ꢀC to room temperature for 6 h gave the
a- and b-methyl glycosides 33 (75%) and 34 (80%), with concomitant hydrolysis of
tert-butyldiphenylsilyl (TBDPS) group. The anomeric mixtures 33 and 34 on reaction
with TBDPSCl and imidazole in dry CH2Cl2 at 0 ꢀC to room temperature for 2 h
afforded the a-anomers 35a (33%)=36a (29%) and b-anomers 35b (49%)=36b (44%)
(Scheme 5).
The b-anomers 35b and 36b on reaction with NaH, CS2, and MeI in THF at
0 ꢀC to room temperature for 2 h furnished xanthates 27 (90%)=28 (70%), which
on radical cyclization independently under standard reaction conditions using
n-Bu3SnH and AIBN (catalyst) in dry benzene at reflux for 12 h afforded 23
(69%)=24 (71%) (Scheme 6).

SYNTHESIS OF ETHISOLIDE AND ISO-AVENACIOLIDE
1775
Scheme 5. Synthesis of intermediates of 35 and 36.
Scheme 6. Synthesis of 23 and 24.
EXPERIMENTAL
Solvents were dried over standard drying agents and freshly distilled prior to
use. All commercially available chemicals were used without further purification.
1
All reactions were performed under nitrogen. H NMR and 13C NMR spectra were
measured with Varian Gemini FT 200-MHz, Bruker Avance 300-MHz, Unity
400-MHz, and Inova 500-MHz spectrometers with Tetramethylsilane (TMS) as
internal standard for solutions in CDCl3. J values are given in hertz. Chemical shifts
were reported in parts per million (ppm) relative to solvent signal. All column chro-
matographic separations were performed using silica gel (Acme’s, 60–120 mesh).
Organic solutions were dried over anhydrous Na2SO4 and concentrated below
40 ꢀC in vacuo. IR spectra were recorded on at Perkin-Elmer IR-683 spectrophot-
ometer with NaCl optics. Optical rotations were measured with JASCO DIP 300
digital polarimeter at 25 ꢀC. Mass spectra were recorded on CEC-21-11013 or
Finnigan Mat 1210 double focusing mass spectrometers operating at a direct inlet
system or LC=MSD Trap SL (Agilent Technologies).
(3aR,4S,6R,6aR)-4-Ethyl-hexahydro-6-methoxy-3-methylenefuro
[3,4-b]furan (8)
Tf2O (0.49 mL, 3.00 mmol) was added to a solution of 17b (0.70 g, 2.50 mmol)
and pyridine (0.40 mL, 5.00 mmol) in CH2Cl2 (4 mL) at ꢁ20 ꢀC and stirred for

1776
G. V. M. SHARMA AND D. H. CHARY
30 min. It was decanted, dissolved in aqueous NaHCO3 solution (6 mL), and
extracted with CH2Cl2 (2 ꢂ 10 mL). Combined organic layers were washed with
aqueous NaHCO3 solution (5 mL), water (5 mL), 2 N aqueous HCl (5 mL), and brine
(5 mL). The organic layer was dried (Na2SO4) and evaporated to give 19 (0.98 g,
95%) as a yellow syrup, which was used as such for the next reaction.
DBU (0.70 mL, 4.61 mmol) was added to a stirred solution of 19 (0.95 g,
2.30 mmol) in dry DMSO (5 mL) at 0 ꢀC and stirred for 12 h. Reaction mixture
was extracted with EtOAc (2 ꢂ 10 mL) and washed with water (5 mL) and brine
(5 mL). It was dried (Na2SO4) and evaporated to afford 21a as a light yellow liquid,
which was used as such for the next reaction.
n-Bu3SnH (0.51 mL, 1.91 mmol) and AIBN (cat.) were added to a solution of
21a (0.25 g, 0.95 mmol) in dry benzene (25 mL) under N2 atmosphere at reflux and
heated at reflux for 12 h. The reaction mixture was cooled to room temperature,
the solvent was evaporated under reduced pressure, and the residue was purified by
column chromatography (60–120 silica gel, ethyl acetate–petroleum ether, 0.9:9.1)
25
to give 8 (0.13 g, 71%) as a colorless liquid; ½aꢃD ¼ ꢁ49:2 (c 0.23, CHCl3); IR (neat):
3437, 2926, 2856, 1737, 1219, 1051, 769 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 1.01 (t,
3H, J ¼ 7.3 Hz, CH3), 1.49 (m, 2H, CH2), 3.19 (t, 1H, J ¼ 7.1 Hz, H-3a), 3.29 (s, 3H,
OCH3), 3.94 (m, 1H, H-4), 4.16 (m, 2H, OCH2), 4.53 (d, 1H, J ¼ 6.4 Hz, H-6a), 4.81
(s, 1H, H-6), 4.92 (d, 1H, J ¼ 1.7 Hz, olefinic) 5.06 (d, 1H, J ¼ 1.5 Hz, olefinic);13C
NMR (75 MHz, CDCl3): d 147.1, 107.7, 96.2, 88.5, 80.9, 72.6, 54.1, 50.0, 24.3, 11.4.
HRMS (EI): m=z calculated for C10H17O3(MþþH) 185.1177; found 185.1170.
(3aR,4S,6R,6aS)-Hexahydro-6-methoxy-3-methylene-4-octylfuro[3,4-
b]furan (9)
To a solution of 18b (0.80 g, 2.19 mmol) and pyridine (0.35 mL, 4.38 mmol) in
CH2Cl2 (10 mL) at ꢁ20 ꢀC, Tf2O (0.40 g, 2.63 mmol) was added and stirred for
30 min. Workup as described for 19 gave 20 (1.01 g, 93%) as a yellow syrup, which
was used as such for the next reaction.
DBU (0.49 mL, 3.21 mm) was added to a stirred solution of 20 (0.80 g,
1.60 mmol) in DMSO (5 mL) at 0 ꢀC and stirred for 12 h. Workup as described
for 21a afforded 22a as a light yellow liquid, which was used as such for the next
reaction.
n-Bu3SnH (0.93 mL, 3.47 mmol) and AIBN (cat.) were added to a solution of
22a (0.60 g, 1.73 mmol) in dry benzene (25 mL) under N2 atmosphere at reflux and
heated at reflux for 12 h. Workup as described for 8 and purification of the residue
by column chromatography (60–120 silica gel, ethyl acetate–petroleum ether,
25
0.9:9.1) gave 9 (0.30 g, 65%) as a colorless liquid; ½aꢃD ¼ ꢁ192:8 (c 0.14, CHCl3);
IR (neat): 3412, 2891, 2797, 1764, 1176, 1083, 804 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 0.88 (t, 3H, J ¼ 6.1 Hz, CH3), 1.27 (m, 14H, 7 ꢂ CH2), 3.17 (t, 1H, J ¼ 6.8 Hz, H-3a),
3.29 (s, 3H, OCH3), 4.02 (m, 1H, H-4), 4.17 (s, 2H, OCH2), 4.50 (d, 1H, J ¼ 6.4 Hz,
H-6a), 4.81 (s, 1H, H-6), 4.92 (s, 1H, olefinic), 5.06 (s, 1H, olefinic); 13C NMR
(75 MHz, CDCl3): d 145.3, 111.7, 105.1, 82.5, 79.9, 71.6, 61.0, 55.2, 31.9, 29.7, 26.8,
26.3, 22.6, 14.1. HRMS (ESI): m=z calculated for C16H29O3(Mþ þ H) 269.2038;
found 269.2072.

SYNTHESIS OF ETHISOLIDE AND ISO-AVENACIOLIDE
1777
(((3aS,4R,6S,6aR)-Hexahydro-4-methoxy-3-methylenefuro[3,4-b]
furan-6-yl)methoxy)(tert-butyl)diphenylsilane (23)
A solution of 27 (0.80 g, 1.45 mmol) in dry benzene (25 mL) under N2
atmosphere was treated with n-Bu3SnH (0.78 mL, 2.91 mmol) at room temperature
and heated at reflux for 30 min. After 30 min, catalytic amount of AIBN was added
at reflux and stirred for 12 h. Workup as described for 8 and purification of the resi-
due by column chromatography (60–120 silica gel, ethyl acetate–petroleum ether,
25
1.2:8.8) afforded 23 (0.43 g, 69%) as a colorless liquid; ½aꢃD ¼ ꢁ45:7 (c 0.1, CHCl3);
IR (neat): 2864, 1756, 1612, 1387, 1234, 1113, 768 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 1.05 (s, 9H, C(CH3)3), 3.40 (s, 4H, H-3a and OCH3), 3.77 (d, 2H,
J ¼ 3.3 Hz, OCH2), 4.25–4.38 (m, 2H, allylic-CH2), 4.49–4.54 (m, 1H, H-6), 4.68
(dd, 1H, J ¼ 2.2, 6.7 Hz, H-6a), 5.05 (br.s, 2H, olefinic), 5.12 (d, 1H, J ¼ 6.0 Hz,
H-4), 7.34–7.42 (m, 6H, Ar-H), 7.64–7.70 (m, 4H, Ar-H);13C NMR (75 MHz,
CDCl3): d 146.2, 135.5 (4C), 129.67 (2C), 127.6 (4C), 106.7, 105.9, 85.9, 84.1, 73.4,
64.5, 55.6, 54.9, 26.7, 19.2. HRMS (ESI): m=z calculated for C25H32O4NaSi
(Mþ þ Na) 447.19621; found 447.19692.
(((3aS,4R,6R,6aR)-Hexahydro-4-methoxy-3-methylenefuro[3,4-
b]furan-6-yl)methoxy)(tert-butyl)diphenylsilane (24)
A solution of 28 (0.12 g, 0.22 mmol) in dry benzene (25 mL) under N2 atmos-
phere was treated with n-Bu3SnH (0.17 mL, 0.43 mmol) at room temperature and
heated at reflux for 30 min. After 30 min, a catalytic amount of AIBN was added
at reflux and stirred for 12 h. Workup as described for 8 and purification of the resi-
due by column chromatography (60–120 silica gel, ethyl acetate–petroleum ether,
25
1.2:8.8) afforded 24 (0.07 g, 71%) as a colorless liquid; ½aꢃD ¼ ꢁ32:7 (c 0.31, CHCl3);
1
IR (neat): 2934, 2889, 1744, 1674, 1426, 1218, 1165, 767 cmꢁ1; H NMR (300 MHz,
CDCl3): d 1.05 [s, 9H, C(CH3)3], 3.32 (s, 1H, H-6), 3.39 (s, 3H, OCH3), 3.83 (d, 2H,
J ¼ 4.1 Hz, OCH2), 4.25 (m, 2H, allylic-CH2), 4.61–4.68 (m, 2H, H-6a and H-3a),
4.96 (d, 1H, J ¼ 6.0 Hz, H-4), 5.02 (br.s, 2H, olefinic), 7.34–7.42 (m, 6H, Ar-H),
7.70–7.72 (m, 4H, Ar-H);13C NMR (75 MHz, CDCl3): d 145.9, 135.6 (2C), 133.2
(2C), 129.6 (2C), 127.6 (4C), 106.9, 105.1, 85.1, 76.9, 73.6, 63.4, 55.2, 54.5, 26.7,
19.1. HRMS (ESI): m=z calculated for C25H32O4NaSi (Mþ þNa) 447.19621; found
447.19538.
CONCLUSION
The cis-fused bicyclic systems were successfully synthesized by 5-exo-dig rad-
ical cyclization from appropriate vinyl radical intermediates en route to the formal
synthesis of ethisolide and iso-avenaciolide. The concomitant introduction of exo-
methylene group and inversion of adjacent sterocenter took place while creating
cis-fused bicyclic systems. For the creation of diversity of bicyclic systems with dif-
ferent side chains and different substitutions in furonoside ring at C-4 position, two
cis-fused bicyclic systems were synthesized by 5-exo-dig cyclization from D-xylose
and L-arabinose. The yields of the products in the present study are comparable
to the earlier reports.

1778
G. V. M. SHARMA AND D. H. CHARY
FUNDING
H. C. acknowledges the financial support in the form of a research fellowship
from the Council of Scientific and Industrial Research (CSIR), New Delhi, India.
Both authors thank CSIR for financial support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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Asymmetry 2001, 12, 829–837.