Intramolecular base-free sonogashira reaction for the synthesis of benzannulated chiral macrocycles embedded in carbohydrate templates

Article abstract of DOI:10.1002/adsc.201100988

A base-free, intramolecular Sonogashira reaction-based general approach has been established for the diversity-oriented synthesis (DOS) of fused bi- and tricyclic systems containing benzannulated, 10- to 13-membered chiral macrocycles embedded in carbohydrate templates. Macrocycles with different ring sizes have been prepared by pre-designing the chiral building blocks. Base-sensitive groups like acetyl and TBDPS survived the reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201100988

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DOI: 10.1002/adsc.201100988
Intramolecular Base-Free Sonogashira Reaction for the Synthesis
of Benzannulated Chiral Macrocycles Embedded in Carbohydrate
Templates
Altaf Hussain,a Syed Khalid Yousuf,a Deepak Kumar,a Malikharjunarao Lambu,a
Baldev Singh,a Sudip Maity,b and Debaraj Mukherjeea,*
a
NPC-division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu – 180001, India
Fax : (+91)-191-256-9111; phone: (+91)-191-256-9000; e-mail: dmukherjee@iiim.ac.in
CMFIR, Dhanbad, Jharkhand, India
b
Received: December 20, 2011; Revised: March 27, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100988.
Abstract: A base-free, intramolecular Sonogashira
reaction-based general approach has been estab-
lished for the diversity-oriented synthesis (DOS) of
fused bi- and tricyclic systems containing benzannu-
lated, 10- to 13-membered chiral macrocycles em-
bedded in carbohydrate templates. Macrocycles
with different ring sizes have been prepared by pre-
designing the chiral building blocks. Base-sensitive
groups like acetyl and TBDPS survived the reaction
conditions.
medium sized (8- and 9-membered) rings with embed-
ded carbohydrates.[6–9] However, no general approach
has hitherto been reported for the appendage of ben-
zannulated carbohydrates embedded in 10- to 13-
membered macrocycles. Hence, the development of
new synthetic approaches for the diversity-oriented
synthesis (DOS) of these skeletons continues to be an
engaging area of contemporary chemical research.
Following our recent success in the development of
novel catalytic synthetic strategies in carbohydrate
chemistry for the generation of new chemical enti-
ties,[10] herein we report the establishment of base-
free, heterogenous Pd-catalysed intramolecular Sono-
gashira reaction for the synthesis of carbohydrate-
fused benzannulated chiral macrocycles. Pd-catalysed
intramolecular Sonogashira coupling has been exten-
sively utilised for construction of the structural frame-
work of natural products and pharmaceuticals.[11,12]
Keywords: benzannulated macrocycles; carbohy-
drates; heterogeneous catalysis; protection–depro-
tection; Sonogashira reaction
Macrocyclic structures constitute an integral compo- However, its use for the construction of rigid macro-
nent of numerous biologically active natural and syn- cycles with a defined stereochemistry is not well ex-
thetic compounds,[1] attributing diverse functionality ploited. The only report involves the generation of
and stereochemical complexity to the parent mole- cyclic peptides under a smooth, copper-free coupling
cules.[2] The development of antibiotic resistance in reaction.[13] Our synthetic strategy is based upon the
micro-organisms justifies the search for new synthetic build/couple/pair approach.[14] The build step involves
approaches for the synthesis of unnatural macrocycle
analogues for possible application as antibiotics.[3] In
view of their specific chemical properties, carbohy-
drate-fused bicyclic systems containing medium- to
large-sized heterocyclic rings provide a class of mole-
cules with promising therapeutic potential but pre-
senting formidable synthetic challenges.[4,5] Synthetic
strategies for the construction of these compounds
have always fascinated chemists, leading to the devel-
opment of new elegant methodologies. A number of
synthetic routes including ring-closing metathesis
(RCM) as well as radical and Heck cyclisations have
been successfully employed for the construction of Figure 1. General structure of chiral building blocks.
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Scheme 1. Reagents and conditions: (a) BnBr, TBAB, DCM:NaOH, room temperature, 3–5 h; (b) 70% AcOH in H2O; (c)
trityl chloride, Py; (d) propargyl bromide, TBAB, DCM:NaOH, room temperature, 3–5 h; (e) 80% AcOH in water, 658C;
(f) 2-bromobenzyl bromide, TBAB, DCM:NaOH, room temperature, 3–5 h; (g) silica-supported NaIO4; (h) NaBH4, dry
MeOH; (i) PDC, Ac2O, DCM, reflux; (j) TBDPSCl, imidazole, DMF; (k) TBAF, THF; (l) Ac2O, Py.
the preparation of two types of chiral building blocks nipulated using different protection–deprotection and
A (furan) and B (pyran) based upon the sugar tem- glycosylation techniques (Scheme 2). It was found
plate (Figure 1).
that templates for 10- and 12- or 11- and 13-memberd
All the building blocks were prepared from simple, macrocycles can be obtained based upon the substrate
commercially available and relatively cheaper sugar used.
derivatives. For the synthesis of 10-, 11- and 12-mem-
With all these building blocks in hand, we were
bered furan embedded macrocycles, we designed dif- ready to attempt the key coupling step to generate
ferent scaffolds (Scheme 1) which could be synthes- the targeted benzannulated macrocycles. The Sonoga-
ised by strategic installation of functional groups shira reaction is generally carried out in an organic
using the same reaction conditions, but by adjusting solvent such as an amine, benzene, THF, or DMF in
the order of the reaction steps.
In general, the syntheses of furan-based building amine base (where necessary), and a homogeneous
blocks 2–11 involve deprotection of acetonide using palladium catalyst such as Pd(PPh3)4 or
acetic acid and water, selective protection of primary Pd(PPh3)2Cl2. But this makes the separation and re-
the presence of copper(I) iodide as a co-catalyst, an
AHCTUNGTRENNUNG
[16]
AHCTUNGTRENNUNG
hydroxy group by trityl/TBDPS/acetyl group followed covery of the catalyst tedious and often results in high
by propargylation, detritylation, and finally benzyla- palladium contamination of the products. The ideal
tion by using a specific bromobenzyl derivative. How- synthesis of a diverse small library is one in which the
ever, the synthesis of allose derivative 7 involves addi- diversity is achieved in the most efficient manner and
tional steps of 3-OH oxidation of A1 with PDC fol- this represents a formidable challenge to synthetic
lowed by NaBH4 reduction to get the inversion prod- chemists. In order to overcome the above-mentioned
uct.[15]
drawbacks of Pd-catalysed Sonogashira coupling reac-
For the synthesis of pyran-based building blocks, d- tions, heterogeneous solid-supported palladium cata-
glucal (10) and a-d-methyl glucoside (13) were ma- lysts have been used.[17] Therefore, we developed
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Intramolecular Base-Free Sonogashira Reaction for the Synthesis of Benzannulated Chiral Macrocycles
Scheme 2. Reagents and conditions: (a) NaH, DMF, benzyl bromide 08C; (b) m-CPBA, CHCl3, room temperature, N2 atm.
(c) 2-bromobenzyl bromide (for 12a) or 4-bromobenzyl bromide
ACHTUNGTRNEN(UNG for 12b), (d) propargyl alcohol, BF3·Et2O, 0 8C TBAB,
DCM:NaOH, room temperature, 3-5 h; (e) PhCH(OMe)2, CSA, room temperature, 5 h; (f) BnBr, NaH, 08C; (g) 80%
AHCTUNGTRENNUNG
AcOH in H2O; (h) Py, trityl chloride 658C; (i) 2-bromobenzyl bromide (for 15a) or 4-bromobenzyl bromide (for 15b),
TBAB, DCM:NaOH, room temperature; (j) 80% AcOH in H2O, 60 8C; (k) propargyl bromide, DCM:NaOH (aq.), TBAB,
room temperature.
Table 1. Comparison of surface area and basicity of pre-
pared catalysts.
alumina as the solid support so as to create the neces-
sary basic sites within the catalyst itself. Three hetero-
geneous Pd catalysts, namely, (i) P without basic sites,
and (ii) Q and (iii) R having basic sites with varying
total basicity, were prepared. (Table 1).
S.
No.
Catalyst BET surface area[a]
[m2 gÀ1]
Basicity[a]
[m2 gÀ1]
1
2
3
P
Q
R
88.97
238.86
238.86
6.80
17.0
25.7
In order to check the efficacy of the catalysts pre-
pared, the activities were examined in a standard re-
action. A furan-based building block 3 was allowed to
undergo the coupling step to yield the targeted mac-
rocyclic product 1B (Table 2). The formation of prod-
uct was confirmed through spectroscopic analysis. The
disappearance of the acetylenic proton signal (d=
[a]
Measured with the help of CHEMBET-3000 apparatus
under a nitrogen environment.
1
2.52) in H NMR and the appearance of an additional
Table 2. Standardisation of the intramolecular cyclisation
quaternary carbon peak (d=75.1) in 13C NMR spectra
of product 1B were in full agreement with the as-
signed structure. The catalyst R with intrinsic basic
sites was found to be the best in terms of reaction
time and yield, leading to the formation of 1B in 85%
yield (entry 3, Table 2). A comparison with the well-
known commercially available Pd catalysts for the
coupling reaction revealed that the catalytic activity
of R is comparable (entry 1, Table 3). It may be noted
that the use of an external base is the prerequisite for
the catalytic activity of commercially available cata-
lysts as only the traces of product 1B were formed in
its absence (entries 3, 5, 7, Table 3).
using the prepared catalysts.
Entry
Catalyst
Yield [%]
1
2
3
P
Q
R
traces
70
85
[a]
Reaction conditions: substrate 3 (100 mg, 0.25 mmol),
CuI (5 mol%), heterogeneous catalyst (100 mg), THF
(5 mL), room temperature, 23 h under an N2 environ-
ment.
The newly prepared catalysts were characterized
(for details see the Supporting Information) through
XRD studies (Figure 2 for catalyst R). The bulk sur-
face area and basicity were determined using various
techniques like TPD of CO2 (Figure 3) and TPR of
a new, cheap and recyclable heterogeneous Pd cata- hydrogen (Figure 4; details in the Supporting Infor-
lyst for this purpose. To avoid the use of an external mation).
amine base, the catalyst was prepared by using basic
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Table 3. Comparison of catalytic activity of catalyst R with commercial products.[a]
Entry
Catalyst
R[b]
Base
Solvent
Temperature [8C]
1
2
3
4
5
6
7
no ext. base
Et2NH
no ext. base
Cs2CO3
no ext. base
ACHTUNGTRENNUNG
THF
DMF
DMF
DMF
DMF
THF
THF
r.t.
120
120
r.t.
r.t.
r.t.
r.t.
85
88
trace
84
trace
89
[c]
Pd
Pd(PPh3)2[Cc]l2
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(PPh3)4[c]
Pd(PPh3)4
N
trace
[a]
Reaction conditions: substrate (100 mg, 0.25 mmol), CuI (5 mol%), catalyst, solvent (5 mL), room temperature, under an
N2 environment.
100 mg.
5 mol%.
[b]
[c]
Figure 2. XRD diffractogram of catalyst R.
With this newly developed catalyst and standar-
Encouraged by the results, we allowed pyran-based
dised reaction procedure in hand, the furan-based scaffolds to undergo coupling using the same standar-
scaffolds 2–11 were then subjected to the coupling dised reaction conditions to yield the desired 10- to
step using intramolecular Sonogashira reaction. All 13-membered macrocyclic compounds in excellent
the reactions proceeded smoothly leading to the for- yield (Table 4, 2A–2D). On a large scale (1 g of the
mation of 10-, 11- and 12-membered benzannulated substrate), the reaction proceeded in a similar manner
macrocyclic products in good to excellent yields even with a lower catalytic loading (0.6 g), thus
(Table 4, 1A–1J). Both cis- (entries 1–7, 9, 10, making the process amenable to easy scale-up.
Table 4) and trans- (entry 8, Table 4) fused ring junc-
The efficacy and robustness of our catalytic system
tions were generated using pre-designed building became more obvious when the recyclability was
blocks. The mildness of the reaction protocol is note- checked. The catalyst was recovered by filtration after
worthy as supported by the survival of base-sensitive each experiment and could be reused for cyclisation
silyl and acetyl groups (entries 9 and 10).
in more than three successive reactions without a sig-
nificant loss of catalytic activity (Figure 5).
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Intramolecular Base-Free Sonogashira Reaction for the Synthesis of Benzannulated Chiral Macrocycles
Figure 5. Recyclability of catalyst R in the cyclisation of 3.
process is versatile and can be used to generate tar-
geted molecules of choice by merely swapping the po-
sition of alkynyl and aryl groups involved in the reac-
tion. The recyclability and easy handling of the cata-
lyst are the merits of the process. The downstream
products are of biological relevance and are being
screened for cytotoxicity and antimicrobial activities.
Figure 3. CO2-TPD of supports of catalyst P, Q and R.
Finally, metallic Cu contamination in the product
after filtration was tested by atomic absorption spec-
trometry. It was below the detection level in the prod-
ucts up to run 3, and only in the range of ~64.8 ppb
after 3 cycles.
In summary, a library of benzannulated carbohy-
drate-based macrocycles has been synthesised using
a base-free intramolecular Sonogashira reaction. The
Experimental Section
General Procedure for the Preparation of Pd Catalyst
Preparation of the basic support: A solution of K2CO3
(30 g) in water was added dropwise to aluminium oxide
(100 g) with vigorous stirring. During the entire process the
temperature was maintained between 45–608C. The mixture
was kept overnight and then evaporated to dryness. The
Figure 4. Hydrogen TPR of catalyst R.
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Table 4. Synthesis of benzannulated medium-sized macrocycles via the intramolecular Sonogashira reaction.
Entry
1
Substrate[a]
Product[b]
Time [h]
Yield [%][c]
20
85
2
3
23
24
85
90
4
22
91
5
6
23
24
91
90
7
8
24
25
94
94
9
25
88
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Intramolecular Base-Free Sonogashira Reaction for the Synthesis of Benzannulated Chiral Macrocycles
Table 4. (Continued)
Entry
10
Substrate[a]
Product[b]
Time [h]
24
Yield [%][c]
82
11
25
21
87
85
12
13
20
22
84
88
14
[a]
Reaction conditions: substrate (100 mg, 0.25 mmol), CuI (5 mol%), heterogeneous catalyst R (100 mg), THF (5 mL),
room temperature.
Characterised through spectroscopic analysis.
Isolated yield after column chromatography
[b]
[c]
product was initially dried at 1108C, then calcined at 4508C
tate, dried over anhydrous Na2SO4 and purified by column
chromatography on silica gel using petroleum ether-ethyl
acetate (91:9) as the eluent to obtain the pure product 1B;
yield: 85%. 1H NMR (400 MHz, CDCl3): d=1.33 (s, 3H,
CH3), 1.54 (s, 3H, CH3), 3.31 (dd, J=6.5, 9.3 Hz, 1H, H-5b),
3.86 (dd, J=5.6, 9.8 Hz, 1H, H-5a), 4.03 (d, J=3.1 Hz, 1H,
H-3), 4.20 (d, J=16.17 Hz, 1H, H-6a), 4.29 (d, J=16.17 Hz,
1H, H-6b), 4.40 (dt, J=3.2, 6.0 Hz, 1H, H-4), 4.58 (d, J=
12.7 Hz, 1H, H-15b), 4.68 (d, J=3.8 Hz, 1H, H-2), 4.73 (d,
J=12.7 Hz, 1H, H-15a), 5.95 (d, J=3.8 Hz, 1H, H-1), 7.16
(dt, J=7.6, 1.5 Hz, 1H, H-11), 7.30–7.34 (m, 1H, H-12), 7.42
(d, J=1.1, 6.5 Hz, 1H, H-13), 7.54 (m, 1H, H-10); 13CNMR
(500 MHz, CDCl3): d=26.4 (CH3), 26.8 (CH3), 59.1 (C-6),
67.7 (C-5), 70.7 (C-8), 71.4 (C-15), 75.2 (C-7), 79.0 (C-4),
prior to the reaction and stored in vacuum desiccators.
Palladium loading: To a solution of PdCl2 (1.52 g) in ace-
tone (50 mL) were added PPh3 (4.53 g in acetone) and the
basic support (2.00 g) prepared above. The mixture was
stirred for 5–8 h, then evaporated and washed with water
under suction. The residue was kept overnight at room tem-
perature and heated at 808C for 5–6 h to get the desired cat-
alyst (R).
Typical Procedure for Cyclisation via Intramolecular So-
nogashira Reaction; Synthesis of 1B
The substrate 3 (100 mg, 0.25 mmol) was dissolved in dry
THF (2.0 mL). Diisopropylamine (1 equiv., 35.07 mL) was
added to the above solution followed by the addition of het-
erogeneous Pd catalyst (R) containing basic support
(100 mg) and co-catalyst CuI (5 mol%). The reaction mix-
ture was allowed to stir for 23 h under a nitrogen atmos-
phere. After ascertaining completion of the reaction by
TLC, the mixture was filtered and the solvent was evaporat-
ed under vacuum. The product was extracted with ethyl ace-
82.1 (C-2), 82.3 (C-3), 105.2 (C-51), 111.9 (CACHTNUGTRNEG(UN CH3)2), 122.73
(C-9),126.7 (C-12), 129.3 (C-11), 129.3 (C-13), 132.6 (C-10),
136.8 (C-14); ESI-MS: m/z=339 [M+Na]+; anal. calcd. for
C18H20O5: C 68.3, H 6.4; found: C 68.4, H 6.4
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Intramolecular Base-Free Sonogashira Reaction for the
Synthesis of Benzannulated Chiral Macrocycles Embedded
in Carbohydrate Templates
9
Adv. Synth. Catal. 2012, 354, 1 – 9
Altaf Hussain, Syed Khalid Yousuf, Deepak Kumar,
Malikharjunarao Lambu, Baldev Singh, Sudip Maity,
Debaraj Mukherjee*
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