Synthesis of carbohydrate fused chiral macrocyclic benzolactones through Sonogashira reaction

Article abstract of DOI:10.1039/c3ra43827a

Synthesis of 10-, 11- and 12-membered chiral benzolactones fused to furanose/pyranose sugars has been achieved in good to excellent yields using an intramolecular Sonogashira reaction. Positions 1-2, 3-5, 3-6 and 5-6 of sugar were utilized for the constru

Full text of DOI:10.1039/c3ra43827a

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Synthesis of carbohydrate fused chiral macrocyclic
benzolactones through Sonogashira reaction†
Cite this: RSC Adv., 2013, 3, 19899
Altaf Hussain,ab Mallikharjuna Rao L,ab Deepak K. Sharma,ab Anil K. Tripathi,b
b
ab
*
Baldev Singh and Debaraj Mukherjee
Received 22nd July 2013
Accepted 2nd September 2013
DOI: 10.1039/c3ra43827a
www.rsc.org/advances
Synthesis of 10-, 11- and 12-membered chiral benzolactones fused to macrolactones: (1) lactonization strategies (cyclization
furanose/pyranose sugars has been achieved in good to excellent precursor must contain alcoholic and carboxyl groups as
yields using an intramolecular Sonogashira reaction. Positions 1–2, 3– shown in Fig. 2) and (2) non-lactonization strategies (cycliza-
5, 3–6 and 5–6 of sugar were utilized for the construction of the tion precursor need not contain alcoholic and carboxyl groups
macrocycles. The requisite furanose/pyranose scaffolds were as shown in Fig. 3). The lactonization strategies include: (i) the
synthesized utilising conventional protection–deprotection strate- Corey–Nicolaou S-pyridyl ester lactonization method,8 (ii) the
gies like benzylation, tritylation, detritylation, EDC coupling, prop- Masamune thiol ester activation method,9 (iii) the Mukaiyama
argylation, etc.
onium salt method,10 (iv) the Yamaguchi mixed-anhydride
method,11 (v) the Keck–Steglich DCC/DMAP/HCl activation
method,12 (vi) the Mitsunobu alcohol activation method,13
and (vii) the Shiina benzoic anhydride method,14 while the
non-lactonization strategies include: (i) ring closing metath-
esis (RCM),15,16 (ii) multi-component Ugi reaction,17 (iii)
Macrolactones are widespread in nature and possess promising
pharmacological properties such as enzyme inhibitory activity.1
Macrocyclic benzolactones, in particular, are an ever-growing
class of natural products with potential therapeutic and agro-
chemical applications.2 For example, each of the macrocyclic
benzolactones shown in Fig. 1 exhibit characteristic and unique
type of biological activities.3–6 Thus, the benzolactone core is
clearly a biologically signicant structural motif.
The synthesis of the macrocyclic framework is one of the
important processes for producing natural and synthetic
compounds useful in organic chemistry.7 Two types of meth-
odologies are mainly employed for the synthesis of
Fig. 1 Biologically significant naturally occurring macrocyclic benzolactones.
aAcademy of Scientic & Innovative Research (AcSIR), India. E-mail: dmukherjee@iiim.
ac.in; Fax: +91-191-2569111
bCSIR-IIIM [Indian Institute of Integrative Medicine], Canal Road, Jammu (J & K),
180001, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra43827a
Fig. 2 Lactonization strategies for the synthesis of macrolactones.
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Scheme 1 Scaffolds for Sonogashira reaction utilizing 3–5 and 3–6 positions of
sugar. Reagents and conditions: (a) propargyl bromide, DCM : aq. NaOH, TBAB, 3
h, rt, 80%; (b) 70% AcOH in H2O, 8 h, rt, 78%; (c) R–Cl, Py, 12 h [R ¼ trityl (3a, 65%)
or tosyl (3b, 81%)] or TBDPSCl (for compound 3c), imidazole, dry DMF, N2 atm, rt,
85%; (d) or (d0) or (f00 ) 2-bromobenzoic acid, EDC, DMAP, DCM, 3 h, 80%; (e0) or
(e00) 80% AcOH in H2O, 65 ꢀC, 12 h, 60%; (f0 ) R–Br [R ¼ benzyl (6a), 4-methox-
ybenzyl (6b), methyl (6c)], NaH, DMF, 0 ꢀC, 5–6 h, 85%; (d00) BnBr, DCM : NaOH
(aq.), TBAB, rt, 3 h, 80%.
Fig. 3 Non-lactonization strategies for the synthesis of macrolactones.
bis-electrophilic iodide or aldehyde (Madsen and Clausen)
macrocyclization,18,19 and (iv) Pd-catalyzed cross coupling.20 In
contrast, there are only a few reports of Sonogashira reaction
being employed for the synthesis of such rings.21–23 However,
Pd-catalyzed ring annulations using carbohydrates for the
synthesis of small sized oxygen and nitrogen containing bi-
cyclic and tri-cyclic benzannulated molecular systems are well
documented in recent literature.24 Moreover, the carbohy-
drates have been used as “off-templates” for the stereoselective
synthesis of chiral g- and d-lactones.25–27 Interestingly, linking
of carbohydrates to the reactive heterocycle increases water
solubility, which is advantageous for bioavailability.28 In
continuation of our interest in synthetic benzannulated carbo-
hydrate based macrocyclic ethers and thioethers29 we therefore
thought of applying similar strategy for the construction of
carbohydrate based macrocyclic benzolactones. In this paper we
demonstrate the feasibility of a modied form of Sonogashira
reaction for the synthesis of unnatural chiral macrocyclic ben-
zolactones (10, 11 and 12 membered rings) fused with furanose/
pyranose sugars. In the process, we discovered a new non-lac-
tonization strategy for the construction of macrocyclic benzo-
lactones as elucidated herein.
used for the preparation of 10 while the intermediate 20
(Scheme 2) was prepared from diacetone allose by doing a
similar sequence of reactions as that for 2. Initial deprotection
of 5–6 isopropylidene unit of 2 followed by NaIO4 cleavage of the
resulting diol led to the formation of an aldehyde which was
subsequently reduced to alcohol 9. Compound 9 was then
subjected to EDC coupling with 2-bromobenzoic acid giving 10
(Scheme 2). Scaffold 100 was prepared similarly using allose-
derived intermediate 20 instead of diacetone glucose (Scheme 2,
for detailed procedures see ESI†).
Utilizing 5–6 position of sugar: Benzylation at 3-position of 1
followed by deprotection of 5–6 isopropylidene unit and then
tritylation at primary OH of diol gave 12. The intermediate was
propargylated at 5-OH, detritylated and subjected to EDC
coupling with 2-bromobenzoic acid to generate the scaffold 14
(Scheme 3, for detailed procedures see ESI†).
Utilizing 1–2 position of sugar: Tri-O-benzyl-D-glucal 15 was
treated with m-CPBA and then acetylated to give 16, which on
propargylation at anomeric position gave 17. This was then
deacetylated at 2-position and submitted to EDC coupling to
build the scaffold 18 (Scheme 4, for detailed procedures see
ESI†).
We prepared the required scaffolds from simple, commer-
cially available and cheap starting materials like diacetone
glucose and D-glucal. In order to bring diversity in their struc-
tures, we utilized different positions of starting sugars, viz. 3–5,
3–6, 5–6 and 1–2 positions (Schemes 1–4).
Utilizing 3–5 and 3–6 positions of sugar: Substrates 4, 6 and 10
were synthesized using 3–5 positions of diacetone glucose
(Schemes 1 and 2) while 8 was prepared using 3–6 positions
(Scheme 1). The substrate 100 was synthesized using 3–5 posi-
tion of diacetone allose by doing a similar sequence reaction
steps. Propargylation of 1 gave 2 which on deprotection of 5–6
isopropylidene unit followed by protection at primary alcoholic
position (C-6 of sugar) gave intermediate 3. This was then
converted to 4a–c, 6a–c and 8 using suitable reaction sequences
Scheme 2 Substrates for Sonogashira reaction utilizing 3–5 position of sugar.
Reagents and conditions: (a/a0) 70% AcOH in H2O, rt, 8 h, 75%; (b/b0) silica
supported NaIO4, DCM, rt, 5 h, 91%; (c/c0) NaBH4, MeOH, 0 ꢀC, 0.5 h, 82%; (d/d0)
as detailed in Scheme 1. Intermediate 2 (from Scheme 1) was 2-bromobenzoic acid, EDC, DMAP, DCM, rt, 3 h, 80%.
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Table 1 List of macrocyclic chiral benzolactones fused with sugars synthesized
using Sonogashira reaction
Entry Substratea
Productb
Time (h) Yieldc (%)
1
25
20
22
25
20
24
25
85
81
87
88
83
80
89
Scheme 3 Substrates for Sonogashira reaction utilizing 5–6 position of sugar.
Reagents and conditions: (a) BnBr, DCM : NaOH (aq.), TBAB, rt, 3 h, 80%; (b) 70%
AcOH in H2O, rt, 8 h 75%; (c) trityl chloride, Py, 65%; (d) propargyl bromide,
DCM : NaOH (aq.), TBAB, rt, 3 h, 80%; (e) 80% AcOH in H2O, 65 ꢀC, 12 h, 60% (de-
tritylation); (f) 2-bromobenzoic acid, EDC, DMAP, DCM, rt, 3 h, 80%.
2
3
4
5
6
7
Scheme 4 Scaffolds for Sonogashira reaction utilizing 1–2 position of sugar.
Reagents & conditions: (a) m-CPBA, CHCl3, rt, 5–8 h, N2 atm, 40%; (b) Ac2O, Py, rt,
2 h, 95%; (c) propargyl alcohol, BF3$Et2O, 0 ꢀC, 12 h, 78%; (d) NaOMe, MeOH, rt,
0.5 h, 95%; (e) 2-bromobenzoic acid, EDC, DMAP, DCM, rt, 3 h, 80%.
The substrates (4, 6, 8, 10, 100, 14 and 18) synthesized above,
containing the required reactive sites (alkyne and aryl halide),
were then cyclized giving macrocyclic benzolactones in 80–90%
yield (entries 1–11, Table 1). The Pd-catalyst used in this reac-
tion is an alumina supported heterogeneous catalyst (charac-
terized in our previous communication, see ref. 29) containing
basic sites on it so that there is no requirement of external base.
Taking the scaffold 10 as a model substrate, we carried out the
reaction using this Pd-catalyst (100 mg for 100 mg of substrate)
and 5 mol% CuI as co-catalyst in dry THF (Scheme 5). The
completion of reaction was checked by TLC which showed the
complete consumption of starting material aer about 25 hours
giving VIII in 90% yield. The product was puried by column
chromatography and fully characterized by 1H and 13C NMR
spectroscopic data.
8
25
25
20
23
90
82
85
86
9
In the 1H NMR spectrum of cyclization precursor 10, the
acetylenic proton signal appears at d 2.44 ppm (encircled as B in
Fig. 4) which is absent in the 1H NMR spectrum of the cyclized
product (VIII). The CH2 proton signals of the propargyl group in
10 (Ha/Hb encircled as A in Fig. 4) appear as two double
doublets at d 4.24 and 4.28 ppm (due to geminal coupling as
well as coupling with terminal C–H proton of propargyl group)
overlapping a doublet-like signal at 4.22 ascribable to H-3, while
in the spectrum of VIII, two doublet signals at d 4.31 and 4.33
ppm (encircled as C in Fig. 4) are observed due to the absence of
terminal C–H proton. Further, there is only one quaternary
carbon signal between d 70–80 ppm (at 78.8 ppm, encircled as D
in Fig. 4) in the 13C NMR spectrum of 10, though that of VIII
10
11
a
Reaction conditions: substrate (100 mg), Pd-catalyst (100 wt%), CuI (5
b
mol%), THF (3.0 mL), rt. Characterized through spectroscopic
analysis. c Isolated yields aer column purication.
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Scheme 5 Ring closure by intramolecular Sonogashira reaction.
showed two such signals (encircled as E in Fig. 4) at d 70.9 and
74.8 ppm.
As an illustration of the utility of the present method, the
synthesis of chiral macrocyclic benzolactones of the type 20 was
taken up from easily available starting materials diacetone
glucose and 2-bromobenzoic acid. The synthetic strategy
involves the preparation of intermediate 9 from diacetone
glucose followed by EDC coupling, Sonogashira coupling and
NaIO4 cleavage of the sugar moiety (Fig. 5).
Fig. 5 Retrosynthetic analysis of benzolactone 20.
carbohydrates. The method has been utilized for the synthesis
of benzolactone 20. The synthesized benzolactones (entries
1–11, Table 1) are under investigation for their anticancer and
antimicrobial activities.
The compound VIII, synthesized above (Schemes 2 and 5),
was treated with TFA–H2O (3 : 1) followed by NaIO4 cleavage of
the resulting sugar diol gave the di-aldehyde 19, which was
Experimental section
reduced with NaBH4 giving benzolactone 20 in 50% yield over Unless otherwise stated, materials were obtained from
three steps as shown in Scheme 6 (for detailed procedures see commercial suppliers and were used without further purica-
ESI†).30
tion. All reactions were performed under nitrogen atmosphere
In summary, a modied form of Sonogashira coupling unless stated otherwise. TLC was performed on pre-coated silica
involving Pd-catalyst containing basic sites was successfully gel plates (F254, 0.25 mm thickness); compounds were visual-
applied for the synthesis of 10, 11 and 12-membered chiral ized by charring with ceric ammonium sulphate–H2SO4 system
benzolactones fused with carbohydrates. The scaffolds required or using UV light. 1H and 13C NMR spectra were recorded on 400
for the reaction were synthesized using conventional protec- MHz and 125 MHz spectrometers respectively. Chemical shis
tion–deprotection strategies. The stereochemistry of the prod- (d) are quoted in ppm and are referenced to TMS as internal
ucts was predened due to the inherent chirality of standard. Removal of solvent in vacuo refers to distillation using
Fig. 4 Selected regions of spectra of cyclization precursor (10) and cyclized product (VIII).
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Scheme 6 Synthesis of benzolactone 20 using the present methodology.
a rotary evaporator attached to an efficient vacuum pump.
Products obtained as solids or syrups were dried under high
vacuum. Solvents used were mainly of LR grade and for reac-
tions dry solvents were used purchased from Sigma Aldrich.
Optical rotation measurements were carried out on Perkin-
Elmer 241 polarimeter.
Typical procedure for cyclization via intramolecular
Sonogashira reaction: synthesis of compound VIII
The cyclization precursor 10 containing alkynyl group and aryl
halide moiety (100 mg, 0.24 mmol) was dissolved in dry THF
(3.0 mL). Heterogeneous Pd-catalyst R (reported in our previous
paper ref. 29) containing basic support (100 wt%) and co-cata-
lyst CuI (5 mol%) were added to the above solution and the
reaction mixture was allowed to stir for several hours at room
temperature under nitrogen environment. Aer ascertaining
completion of the reaction by TLC, the catalyst was ltered and
the solvent was evaporated under vacuum. The reaction mixture
was extracted with ethyl acetate and dried over anhydrous
Na2SO4. Aer evaporation, the product was puried by column
chromatography on silica gel using petroleum ether–ethyl
acetate as the eluent to obtain the pure product VIII as a thick
liquid (72.3 mg, 90%); Rf (45% EtOAc/hexane) 0.50; [a]2D5 ꢁ1.30ꢀ
(c 1.0, CHCl3); IR (CHCl3) 2980, 2938, 2210, 1733, 1588 cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 7.84 (dd, J ¼ 7.4, 2.0 Hz, 1H), 7.66 (dd,
J ¼ 7.7, 1.2 Hz, 1H), 7.44–7.27 (m, 2H), 5.96 (d, J ¼ 3.7 Hz, 1H),
4.63 (d, J ¼ 3.7 Hz, 1H), 4.62–4.58 (m, 1H), 4.56 (dd, J ¼ 7.0, 3.6
Hz, 1H), 4.50 (dd, J ¼ 10.1, 6.0 Hz, 1H), 4.35 (d, J ¼ 16.5 Hz, 1H),
4.30 (d, J ¼ 16.5 Hz, 1H), 4.18 (d, J ¼ 2.9 Hz, 1H), 1.51 (s, 3H),
1.34 (s, 3H); 13C NMR (125 MHz, CDCl3) d 165.7, 134.4, 132.7,
131.7, 131.6, 127.2, 121.9, 112.1, 105.2, 81.9, 81.7, 76.8, 74.8,
70.9, 62.9, 57.9, 26.8, 26.3; ESI MS (m/z): 330 [M+]; Anal. calcd for
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Acknowledgements
Authors are thankful to director Indian Institute of Integrative
Medicine (CSIR-IIIM, Jammu) for providing necessary facilities
and DST for nancial support (Project GAP1145). A.H. is
thankful to UGC (New Delhi) for Fellowship (SRF).
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