An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

Article abstract of DOI:10.3762/bjoc.13.110

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide-alkene building blocks coupled through copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

Full text of DOI:10.3762/bjoc.13.110

An eco-compatible strategy for the diversity-oriented
synthesis of macrocycles exploiting carbohydrate-
derived building blocks
Sushil K. Maurya*1,2,§ and Rohit Rana1,2
Full Research Paper
Open Access
Address:
Natural Product Chemistry and Process Development Division,
Beilstein J. Org. Chem. 2017, 13, 1106–1118.
1
doi:10.3762/bjoc.13.110
CSIR- Institute of Himalayan Bioresource Technology, Palampur,
Himachal Pradesh, 176 061, India and 2Academy of Scientific and
Innovative Research, CSIR- Institute of Himalayan Bioresource
Technology, Palampur, Himachal Pradesh, 176 061, India
Received: 27 December 2016
Accepted: 12 May 2017
Published: 09 June 2017
Email:
This article is part of the Thematic Series "Chemical biology".
Guest Editor: H. B. Bode
Sushil K. Maurya* - skmaurya@ihbt.res.in
*
Corresponding author
§
Phone: +91-1894-230742
© 2017 Maurya and Rana; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
carbohydrate; click chemistry; diversity-oriented synthesis;
macrocycles; ring-closing metathesis
Abstract
An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macro-
cyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative
use of readily available sugar-derived alkyne/azide–alkene building blocks coupled through copper catalyzed azide–alkyne cycload-
dition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility,
mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this
protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13
macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the
macrocyclic library generation.
Introduction
Macrocycles offer very complex molecular architectures with a pounds in which at least two bonds from a monosaccharide
diverse range of ring sizes decorated with many functional residue form a part of the macrocyclic rings and have shown
groups found application in pharmaceuticals, agrochemicals, important biological properties [5-12]. For example, macro-
cosmetics and materials science [1-4]. Carbohydrate-embedded cyclic aminoglycoside analogues have shown binding with the
macrocycles represent an important class of macrocyclic com- trans-activating region (TAR) RNA of the human immunodefi-
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ciency virus (HIV); an attractive target for RNA-based drug oriented synthesis (DOS). These moieties can be easily
discovery [13]. Further, macrocyclic glycolipids have shown furnished with alkyne or azide functionality with routine syn-
phosphatase inhibition, cytotoxicity and antiviral activities thetic transformation protocols that allow facile access to mono-
[
12,14]. Generally, the synthesis of these molecules involves a as well as poly-functionalized derivatives via CuAAC reaction.
multi-step construction of linear precursors incorporating syn- The approach enables the rapid synthesis of carbohydrate conju-
thetically compatible functional groups followed by a cycliza- gates in which the heterocyclic triazolyl ring serves as a shackle
tion in the late stage of the synthesis. The cyclization of the for joining the carbohydrate building blocks. Further, these
linear precursor is usually achieved by utilizing various ring- carbohydrate conjugates decorated with appropriate coupling
closing reactions such as Diels–Alder reactions, [15] aldol reac- partner can be paired through ring closing metathesis (RCM)
tions, [16] copper-catalyzed azide–alkyne cycloaddition, reaction. Carrying out the metathesis processes in green sol-
[
17,18] macrolactonization, macrolactamizations, Staudinger vents is a major challenge. Unfortunately, halogenated solvents
ligation or transition-metal-catalyzed coupling reactions [19]. such as dichloromethane (DCM), 1,2-dichloroethane (DCE) or
Recently, ring-closing alkyne metathesis (RCAM) [20,21] and aromatics such as benzene and toluene are the most frequently
ring closing metathesis (RCM) [22-31] have emerged as very used solvents for metathesis reactions whereas these
powerful tools for macrocyclization including for the prepara- solvents possess serious health and environmental hazards
tion of peptidomimetic [17,18,32] glycosides and macrocyclic [57,58].
glycolipids [11]. Similarly, the copper-catalyzed azide–alkyne
cycloaddition (CuAAC) reaction has found wide application in Here we report a novel application of the popular build-couple-
medicinal chemistry [33], biology [34,35], polymer chemistry pair (B/C/P) strategy [4,18,54,55,59,60] for the synthesis of
[
36], carbohydrates [37-40], peptides [41-44] and in materials sugar embedded macrocycles by iterative use of carbohydrate
science [45-48]. There are several reports wherein different derived building blocks armed with azide/alkyne–alkene func-
strategies have been developed and used for the synthesis of tionalities. The building blocks were coupled via 1,3-dipolar
glycoconjugates [9,49-51], however, the combination of a cycloaddition (click reaction) iteratively through the develop-
CuAAC and a RCM reaction has been used very little and ment of a greener base-free Cu(I)-catalyzed azide–alkyne cyclo-
rarely combinations of these reactions have been used for the addition reaction. The cycloadducts were then converted to
synthesis of sugar-embedded glycoconjugates [52,53]. Further, macrocycles by Ru-catalyzed cyclization reaction using greener
the linear syntheses of macrocycles based on multistep proto- and non-hazards reaction conditions.
cols are not cost-effective and the development of efficient, sus-
tainable, greener and economical methods is highly desired.
Results and Discussion
There are several DOS strategies to generate a collection of
Synthetic methods to produce a diverse collection of macro- diverse molecules among them three-phase build-couple-pair
cycles are rare and usually produce only compounds with a sim- (B/C/P) is one of the most frequently used. The B/C/P strategy
ilar skeleton [20,33]. However, to achieve a higher hit rate involves build phase in which different building blocks were
against a broader range of targets libraries of diverse collec- synthesized incorporating different diversity elements. These
tions of macrocycles are desired [54]. The various diversity ele- different building blocks were then combined together in the
ments of a given library should include the molecular size, couple phase to give the substrates for the next phase. Finally,
shape, heteroatoms, functional groups and stereo chemical com- in the pair phase various functional-group-compatible reactions
plexity for selective binding [4]. The diversity-oriented synthe- were used to generate distinct molecular scaffolds. The build-
sis (DOS), an algorithm in organic chemistry used to generate couple-pair strategy using iterative couple steps (B/C/C/P or
diverse molecules that include two-directional coupling, ring B/C/C/C/P etc.) to increase the diversity of scaffolds accessed
expansion methods, multidimensional coupling and domain from the sets of building blocks has been exploited in recent
shuffling has been used for the synthesis of small molecules and times [59-63]. Also, simple and economical polyfunctional sub-
macrocyclic libraries. Further, several DOS strategies based strates available in abundance from the natural resources are
around build/couple/pair (B/C/P) were developed for the syn- ideal starting materials in DOS, which aims at providing quick
thesis of compound libraries including macrocycles [18,55]. access to libraries of diverse molecules. To exploit the strategy,
Carbohydrates as building blocks are inexpensive and easily it was envisioned that different sugars could serve as precursor
available commercial products and are well-endowed with func- for the necessary alkyne–alkene and azide–alkene functionali-
tionalities which enable them to establish catalytic sites as well ties and could be connected through a sequence of protection-
as secondary binding sites [56]. The abundance of various func- deprotection-functionalization reactions at appropriate position
tional groups in the carbohydrate precursor allows for easy (Figure 1). D-glucose, D-xylose and L-arabinose were used as
access to multiple building blocks by incorporating diversity- the key starting materials for the DOS protocol. It was expected
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Beilstein J. Org. Chem. 2017, 13, 1106–1118.
that each given sugar building block (generated in the building Build phase: preparation of building blocks
phase of the DOS) could be attached through Cu-catalyzed The alkyne–alkene (1a–f) and azide–alkene (2a–d) building
azide–alkyne cycloaddition (CuAAC) reaction (couple phase). blocks were synthesized in multigram scale following known
Noteworthy, herein we utilized the CuAAC reaction as a medi- literature procedures (Figure 2). The experimental details of the
um for coupling different building blocks assembled iteratively various building blocks used for DOS can be found in Support-
to generate a 1,2,3-triazole moiety. This 1,2,3-triazole moiety ing Information File 1.
linked as a spacer due to its inherent properties including
Couple phase: Copper-catalyzed
stability towards acid–base hydrolysis, active participation in
H-bonding, dipole–dipole and π-stacking interactions [37,64- azide–alkyne cycloaddition (CuAAC)
6]. The reaction would then afford a range of acyclic precur- After having ready requisite building blocks our next goal was
6
sors, which could then undergo the intramolecular cyclization to assemble them iteratively to synthesize macrocyclic library
reaction to furnish the macrocyclic compounds (pair phase). In (Scheme 1). All the reactions were monitored after an interval
the pair phase, CuAAC adducts were cyclized using a Ru-cata- of 2 and 4 hours and if required than after 24 hours for the opti-
lyzed metathesis reaction utilizing Grubbs second generation mizations; the conversion in the reaction was calculated by
catalysts under greener reaction conditions (Figure 1).
comparing the ratio of integration of the terminal alkyne proton
Figure 1: Build-couple-pair (B/C/P) strategy for macrocycles.
Figure 2: Different building blocks used for DOS.
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Beilstein J. Org. Chem. 2017, 13, 1106–1118.
Scheme 1: Cycloaddition reaction of alkyne-azide building block.
in the propargyl building block and the characteristic DIPEA under similar conditions resulted in the low yield of
triazole–alkene proton in the cyclo-adducts. The click reaction 48%. It is worth mentioning that the formation of the other
proceeds under various conditions with a plenty of sources of regioisomer was not observed when the reactions were per-
Cu(I) [19]. We have selected copper iodide (CuI) as Cu(I) formed at 90 °C and 110 °C in water using 5 mol % CuI as cata-
source for the CuAAC. Initially we tried the reaction using CuI lyst. These results confirm the essential role of copper required
as catalyst and DIPEA as a base for the cycloaddition of the for the high conversion and selectivity of the products
alkyne (1a) azide and (2a) building blocks in acetonitrile at (Table 1).
room temperature. Pleasingly, the reaction resulted in excellent
conversion (by 1H NMR) in two hours with 70% isolated yield After screening various reaction conditions we found a
whereas addition of triethylamine in acetonitrile resulted in 65% “greener” protocol for the CuAAC reaction in water under mild
yield. For developing greener conditions for the cycloaddition heating and the use of base was eliminated. We have utilized
reaction, a control experiment with alkyne (1a) and azide (2a) this methodology for the synthesis of a range of cycloadducts
in water at room temperature reacted up to 24 hours but in the (3a–m, Table 2) via iterative coupling of carbohydrate derived
absence of copper catalyst and base, only 6% conversion was azide and propargyl building blocks to be used as metathesis
observed (measured by 1H NMR; formation of two products substrates for the synthesis of novel sugar embedded macro-
were observed in the ratio of 77:23). Reaction in water at 70 °C cyclic molecules. Cycloaddition of xylose derived azide build-
under the above conditions gave a 33% conversion with a 63% ing blocks containing a primary azido group (2a) produced sim-
selectivity for the product. Complete disappearance of starting ilar yields (i.e., 3a, 3b and 3d) with xylose and arabinose
materials after 24 hours with the formation of exclusively one derived building blocks containing a propargyl ether group on
product in 45% yield was observed when the reaction was per- the primary OH group (1a and 1c) or xylose derived building
formed at room temperature in water using 5 mol % CuI. block containing a propargyl group on the secondary OH group
Another reaction under similar conditions using CuI and DIPEA (1b). Further, a comparatively lower yield for the cycloaddition
resulted in a lower yield of 35% after 24 hours. The next reac- reaction (3c) was obtained when both building blocks used
tion was performed in water at 70 °C using 5 mol % catalysts in contain a secondary azide group (2b) and a propargyl ether on
absence of a base. Interestingly, we observed complete disap- the secondary OH group (1c). We have observed relatively low
pearance of starting substrate in two hours with an excellent iso- yields (3e and 3f) when we used a combination of glucose (1e
lated yield of 95% for the exclusive product whereas addition of and 2c) and xylose (1b and 2a) derived building block whereas
Table 1: Optimization of the reaction conditions for the cycloaddition.
Entry
Solvent
Base
Catalyst (CuI, mol %)
Temperature
Time (hours) Yield %a
1
2
3
4
5
6
7
8
ACN
ACN
H2O
H2O
H2O
H2O
H2O
H2O
TEA
5
5
–
–
5
5
5
5
ambient
ambient
ambient
70 °C
2
2
65
DIPEA
71
–
24
24
24
24
2
6b (77% selectivity for 3a)c
–
–
33b (63% selectivity for 3a)c
ambient
ambient
70 °C
45
35
95
48
DIPEA
–
DIPEA
70 °C
2
aIsolated yield after column chromatography; bconversion and cproduct selectivity was measured by 1H NMR.
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Table 2: Copper catalyzed azide-alkyne cycloaddition.
Alkyne
Azide
Cycloadducta
Yield %
1a
2a
95
3a
1b
2a
94
3b
1b
2b
75
3c
1c
2a
90
3d
1e
2a
76
3e
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Table 2: Copper catalyzed azide-alkyne cycloaddition. (continued)
1b
2c
78
3f
1e
2c
92
3g
1d
2c
91
3h
1b
2d
85
3i
1a
2d
87
3j
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Beilstein J. Org. Chem. 2017, 13, 1106–1118.
Table 2: Copper catalyzed azide-alkyne cycloaddition. (continued)
1f
2a
95
3k
1e
2d
77
3l
1f
2d
67
3m
aMethod: CuI (5 mol %), water, 70 °C, 2 h.
an excellent yield was obtained (3g and 3h) when both cou- xylose worked better with non-protected OH groups (3i, 3j and
pling partners were derived from glucose (1e, 1d and 2c) irre- 3k) than with protected (3e and 3f). Whereas glucose–glucose
spective of the position of the propargyl group on the primary did work better with protected OH groups (3g and 3h) than with
OH (1e) or secondary OH group (1d). Next we thought of non-protected (3l and 3m).
exploring the effect of protecting groups on the feasibility of the
Pair phase: macrocyclization via Ru-
reaction and the yields and various building blocks with free
OH groups were selected. It is worth mentioning that we did not catalyzed ring closing metathesis (RCM)
observe any significant change in the reaction rate. Yields were In the pair phase the range of linear substrates derived by
relatively high (3i, 3j, 3k and 3l) when we used combination of CuAAC were cyclized via Ru-catalyzed ring closing metathesis
azide and propargyl building blocks containing at least one free reaction (Table 3). In general, RCM conditions used in this
OH group and generally yields were not influenced by the posi- study proved to be very robust and delivered the macrocyclic
tion of the azide or propargyl group onto building blocks. How- product in moderate yields. To begin our RCM endeavor, we
ever, when both building blocks used for the cycloaddition con- performed the macrocyclization reaction on cycloadduct 3a in
taining a free OH group (1f and 2d), the yield for the product dichloromethane (10 mM) heating at 50 °C with 2 mol %
was significantly low (3m). In conclusion, the CuAAC reaction second generation Grubbs catalyst. The reaction was incom-
of xylose derived building blocks gave relatively higher yields plete after two hours and required an additional catalyst loading
(
3a and 3b), except when both building blocks contain a sec- of 2 mol % and 1 mol % after every two hours. However, when
ondary azide and a secondary propargyl ether group (3c). we performed RCM reaction with 5 mol % catalyst under simi-
Cycloaddition of building blocks derived from glucose and lar conditions, the reaction was completed in two hours with
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Table 3: Application of ring-closing metathesis reactions in the synthesis of macrocycles.
Substrate
Methoda (mol %; time; yield)
RCM product
A (5; 2 h; 63%)
B (5; 2 h; 84%)
3a
3b
3c
4a
A (5; 2 h; 85%)
B (5; 2 h; 94%)
4b
A (5; 2 h; 88%)
B (5; 3 h; 94%)
4c
A (5; 2 h; 70%)
B (5; 2 h; 90%)
3d
4d
A (5+5; 3 h; 88%)
B (5+3; 3 h; 40%)
3e
4e
A (5+3; 3 h; 83%)
B (5; 2 h; 39%)
3f
4f
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Table 3: Application of ring-closing metathesis reactions in the synthesis of macrocycles. (continued)
A (5; 2 h; 77%)
B (5+3; 3 h; 92%)
3g
4g
A (5+3; 3 h; 82%)
B (5; 2 h; 92%)
3h
4h
A (5; 2 h; 95%)
B (5; 2 h; 19%)
3i
4i
A (5; 2 h; 84%)
B (5; 2 h; 56%)
3j
4j
A (5; 2 h; 81%)
B (5; 2 h; 96%)
3k
4k
A (5; 2 h; 53%)
B (5; 2 h; 61%)
3l
4l
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Table 3: Application of ring-closing metathesis reactions in the synthesis of macrocycles. (continued)
A (5; 2 h; 40%)
B (5; 2 h; 55%)
3m
4m
aMethods: A: Grubbs second-generation catalyst, CH2Cl2, 50 °C; B: Grubbs second-generation catalyst, ethyl acetate, 75 °C.
6
1% isolated yield. The reaction was performed on the same served in ethyl acetate when the metathesis substrate contains a
substrate (i.e., 3a) under high dilution (1 mM) with 5 mol % free secondary OH group (4i, 4j). Whereas yield was quite high
catalyst at 50 °C in dichloromethane and pleasingly we ob- in ethyl acetate when metathesis substrate contains a free prima-
served completion of the reaction in two hours with 63% isolat- ry OH group (4k). Metathesis yields were relatively higher in
ed yield. Halogenated solvents are not preferred because of as- ethyl acetate when both glucose derived building blocks were
sociated health and safety hazards and “greener” solvents for used containing either one free OH group (4l) or two free
RCM reactions are always required. Ethyl acetate can be chosen OH groups (4m). Most notably RCM reactions in ethyl acetate
as a “green, inexpensive and easily available reaction medium” produce almost the same or even better yields than in dichloro-
for metathesis to synthesize this important yet synthetically methane in most cases (apart from 4e, 4f, 4i, 4j) which confirms
challenging class of molecules [20]. Therefore, our next atten- ethyl acetate as a viable, greener, inexpensive and easily avail-
tion turns towards using ethyl acetate as “greener” solvent for able alternative to the highly hazardous chlorinated solvent
the macrocyclization reaction. A reaction under high dilution which is a traditionally and most frequently used solvent for
(
1 mM) with 5 mol % catalysts at 75 °C in ethyl acetate resulted RCM reactions.
in macrocycle 4a in 84% yield (Table 3). The structure of 4a
was confirmed by 1H NMR based on the disappearance of the To check the effect of purity of the cycloadduct on the rate and
signal corresponding to the allyl group (from the starting mate- feasibility of subsequent RCM reactions and on isolated yield
rial) and appearance of multiplet near δ 5.65 ppm for the obtained in the individual steps, we explored the feasibility of
alkenyl protons. Moreover, the complete structural assignment the RCM reaction without isolating the product at the couple
was done with the help of 2D NMR. It is worth mentioning here phase. Compounds 4e–h were synthesized without purifying the
that the reaction proceeded with excellent selectivity for the respective cycloaddition products. The second generation
trans product (confirmed by 2D NMR).
Grubbs catalyst catalyzed RCM reaction was performed using
the crude substrate in ethyl acetate at 75 °C (Table 4). Interest-
Next we performed the macrocyclization reaction with a range ingly, isolated yields for 4e, 4f and 4h were comparable to the
of metathesis precursors (3b–m) using dichloromethane and yields obtained when they were synthesized in two separate
ethyl acetate solvents. Many of the RCM reactions were clean, steps. However, the yield obtained in case of 4g was significant-
however, to few the catalyst was added portion-wise until ly lower in case of the direct reaction compared to when
completion of the reaction judged by TLC analysis. The results the compound was synthesized via the two-step process
are summarized in Table 3. Relatively better yields were ob- (Table 4).
served in ethyl acetate compared to dichloromethane when the
metathesis precursor consists of pentose (xylose and/or arabi- Lastly, the macrocycle 4m was acetylated in pyridine using
nose) building blocks irrespective of the position of the allyl acetyl chloride and a catalytic amount of DMAP to furnish diac-
group on the primary or secondary OH group (4a–d). However, etate 5. The 1H NMR analysis of 5 clearly showed presence of
yields were significantly lower in ethyl acetate when metathe- two singlets at δ 2.08 and 2.06 ppm integrating for three protons
sis precursors were consisting of glucose with protected each corresponding to acetate methyl groups. Acetate groups
OH groups and xylose building blocks (4e, 4f). Interestingly, were further confirmed by 13C NMR wherein signals corre-
metathesis substrate with both building blocks made-up of sponding to two carbonyl groups apparent at δ 170.9, 170.5
glucose with protected OH groups gave significantly better ppm and two methyl groups at δ 21.0 and 20.9 ppm. The prod-
yield in ethyl acetate (4g, 4h). Considerably low yields were ob- uct was further confirmed by mass spectrometry (Scheme 2).
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Table 4: Feasibility studies of cycloaddition and RCM reaction in single and two-step protocol.
RCM product
Two-step protocola
Direct protocola
CuAAC Yield (%) Grubbs cat. (mol %) RCM yield (%) Combined yield (%) Grubbs cat. (mol %) Yield (%)
4
4
4
4
e
76
78
92
91
(5+3)
5
40
39
92
92
31
30
85
84
(5+5)
32
29
49
80
f
5
5
5
g
h
(5+3)
5
aIsolated yield after column chromatography.
Scheme 2: Acetylation of macrocycle 4m.
Conclusion
References
In conclusion we report a novel and green route to synthesize
sugar embedded macrocycles (in total we have synthesized 13
macrocycles with 17 to 19-membered rings) which involves
CuAAC reaction and Ru-catalyzed RCM reaction. The CuAAC
reaction were performed in water and produce moderate yields.
Thus, we have successfully demonstrated novel application of
build-couple-pair (B/C/P) strategy in DOS and synthesized 13
new macrocycles (4a–m). This synthetic method represents a
significant advantage over current routes for sugar embedded
macrocycles where reactions are rapid, eco-friendly without
compromise in yield and selectivity.
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